Solid forms of a toll-like receptor modulator

ABSTRACT

The present invention provides crystalline forms, solvates and hydrates of 4-amino-2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one, and methods of making.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/051,063, filed Sep. 16, 2014, which is incorporated in its entiretyherein for all purposes.

BACKGROUND

The present disclosure relates generally to crystalline solid forms ofthe antiviral compound4-amino-2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one,processes for making the forms, and their therapeutic methods of use.

The innate immune system provides the body with a first line defenseagainst invading pathogens. In an innate immune response, an invadingpathogen is recognized by a germline-encoded receptor, the activation ofwhich initiates a signaling cascade that leads to the induction ofcytokine expression. Innate immune system receptors have broadspecificity, recognizing molecular structures that are highly conservedamong different pathogens. One family of these receptors is known asToll-like receptors (TLRs), due to their homology with receptors thatwere first identified and named in Drosophila, and are present in cellssuch as macrophages, dendritic cells, and epithelial cells.

There are at least ten different TLRs in mammals. Ligands andcorresponding signaling cascades have been identified for some of thesereceptors. For example, TLR2 is activated by the lipoprotein of bacteria(e.g., E. coli), TLR3 is activated by double-stranded RNA, TLR4 isactivated by lipopolysaccharide (i.e., LPS or endotoxin) ofGram-negative bacteria (e.g., Salmonella and E. coli 0157:H7), TLR5 isactivated by flagellin of motile bacteria (e.g., Listeria), TLR7recognizes and responds to imiquimod and TLR9 is activated byunmethylated CpG sequences of pathogen DNA. The stimulation of each ofthese receptors leads to activation of the transcription factor NF-κB,and other signaling molecules that are involved in regulating theexpression of cytokine genes, including those encoding tumor necrosisfactor-alpha (TNF-α), interleukin-1 (IL-1), and certain chemokines.Agonists of TLR-7 are immunostimulants and induce the production ofendogenous interferon-α in vivo.

There are a number of diseases, disorders, and conditions linked to TLRssuch that therapies using a TLR agonist are believed promising,including but not limited to melanoma, non-small cell lung carcinoma,hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma,myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, hepaticfibrosis, and viral infections such as HBV, Flaviviridae viruses, HCV,HPV, RSV, SARS, HIV, or influenza.

The treatment of Flaviviridae virus infections with TLR agonists isparticularly promising. Viruses of the Flaviviridae family comprise atleast three distinguishable genera including pestiviruses, flaviviruses,and hepaciviruses (Calisher, et al., J. Gen. Virol., 1993, 70, 37-43).While pestiviruses cause many economically important animal diseasessuch as bovine viral diarrhea virus (BVDV), classical swine fever virus(CSFV, hog cholera) and border disease of sheep (BDV), their importancein human disease is less well characterized (Moennig, V., et al., Adv.Vir. Res. 1992, 48, 53-98). Flaviviruses are responsible for importanthuman diseases such as dengue fever and yellow fever while hepacivirusescause hepatitis C virus infections in humans. Other important viralinfections caused by the Flaviviridae family include West Nile virus(WNV) Japanese encephalitis virus (JEV), tick-borne encephalitis virus,Junjin virus, Murray Valley encephalitis, St Louis encephalitis, Omskhemorrhagic fever virus and Zika virus. Combined, infections from theFlaviviridae virus family cause significant mortality, morbidity andeconomic losses throughout the world. Therefore, there is a need todevelop effective treatments for Flaviviridae virus infections.

The hepatitis C virus (HCV) is the leading cause of chronic liverdisease worldwide (Boyer, N. et al. J Hepatol. 32:98-112, 2000) so asignificant focus of current antiviral research is directed toward thedevelopment of improved methods of treatment of chronic HCV infectionsin humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American,October: 80-85, (1999); Gordon, C. P., et al., J. Med. Chem. 2005, 48,1-20; Maradpour, D.; et al., Nat. Rev. Micro. 2007, 5(6), 453-463). Anumber of HCV treatments are reviewed by Bymock et al. in AntiviralChemistry & Chemotherapy, 11:2; 79-95 (2000). Currently, there areseveral antiviral compounds, ribavirin, a nucleoside analog,interferon-alpha (α) (IFN), and sofosbuvir, another nucleoside analog,that are used for the treatment of chronic HCV infections in humans.Ribavirin alone is not effective in reducing viral RNA levels, hassignificant toxicity, and is known to induce anemia. The combination ofIFN and ribavirin has been reported to be effective in the management ofchronic hepatitis C (Scott, L. J., et al. Drugs 2002, 62, 507-556) butless than half the patients given this treatment show a persistentbenefit.

HCV is recognized by innate virus-sensing mechanisms that induce a rapidIFN response (Dustin, et al., Annu. Rev. Immunol. 2007, 25, 71-99). Itis likely that the sources of the IFN are, at least, the infectedhepatocytes and particularly the plasmacytoid dendritic cells (pDC) thathighly express TLR 7 receptors and secrete high amounts of IFN.Horsmans, et al. (Hepatology, 2005, 42, 724-731), demonstrated that aonce daily 7-day treatment with the TLR 7 agonist isatoribine reducesplasma virus concentrations in HCV infected patients. Lee, et al. (Proc.Natl. Acad. Sci. USA, 2006, 103, 1828-1833), demonstrated that TLR 7stimulation can induce HCV immunity by both an IFN and IFN-independentmechanisms. These workers also revealed that TLR 7 is expressed innormal as well as HCV infected hepatocytes. These combined resultssupport the conclusion that stimulation of TLR 7 receptors, such asthrough the administration of a TLR 7 agonist, is a viable mechanism foreffectively treating natural HCV infections. Given the need for moreeffective treatments for HCV infections, there is a need to develop safeand therapeutically effective TLR 7 agonists.

Similarly, despite the existence of efficient vaccines, hepatitis Bvirus (HBV) infection remains a major public health problem worldwidewith 400 million chronic carriers. These infected patients are exposedto a risk of developing liver cirrhosis and hepatocellular carcinoma(Lee, W. M. 1997, N. Eng. J. Med., 337, 1733-1745). Currently, there arebelieved to be approximately 1.25 million chronic hepatitis B carriersjust in the United States, with 200,000 people newly infected each yearby contact with blood or body fluids.

Hepatitis B virus is second to tobacco as a cause of human cancer. Themechanism by which HBV induces cancer is unknown, although it ispostulated that may directly trigger tumor development, or indirectlytrigger tumor development through chronic inflammation, cirrhosis, andcell regeneration associated with the infection.

Hepatitis B virus has reached epidemic levels worldwide. After a two tosix month incubation period in which the host is unaware of theinfection, HBV infection can lead to acute hepatitis and liver damage,that causes abdominal pain, jaundice, and elevated blood levels ofcertain enzymes. HBV can cause fulminant hepatitis, a rapidlyprogressive, often fatal form of the disease in which massive sectionsof the liver are destroyed. Patients typically recover from acute viralhepatitis. In some patients, however, high levels of viral antigenpersist in the blood for an extended, or indefinite, period, causing achronic infection. Chronic infections can lead to chronic persistenthepatitis. Patients infected with chronic persistent HBV are most commonin developing countries. By mid-1991, there were approximately 225million chronic carriers of HBV in Asia alone, and worldwide, almost 300million carriers. Chronic persistent hepatitis can cause fatigue,cirrhosis of the liver, and hepatocellular carcinoma, a primary livercancer.

In western industrialized countries, high risk groups for HBV infectioninclude those in contact with HBV carriers or their blood samples. Theepidemiology of HBV is in fact very similar to that of HIV, whichaccounts for why HBV infection is common among patients with AIDS orHIV-associated infections. However, HBV is more contagious than HIV. Toameliorate suffering and to prolong the lives of infected hosts newcompounds and methods of treating AIDS and attacking the HIV viruscontinue to be sought.

The compound4-amino-2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one,designated herein as Compound I, as described for example in WO2010/077613 and U.S. Pat. No. 8,367,670, has been reported to be aninhibitor of toll-like receptor 7. Moreover, Compound I is beinginvestigated for use in treating HBV and HIV. However, Compound I wasnot previously known in any crystalline form.

BRIEF SUMMARY OF THE INVENTION

In some embodiments, the present invention provides a crystalline formof Compound I having the structure:

and solvates or hydrates thereof.

In some embodiments, the present invention provides a crystalline Form Iof Compound I, and solvates or hydrates thereof, characterized by anX-ray powder diffraction (XRPD) pattern comprising three or more peaksat 5.8, 11.4, 11.6, 17.7, 22.3, 23.9, or 26.0 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the present invention provides a crystalline FormII of Compound I, and solvates or hydrates thereof, characterized by anX-ray powder diffraction (XRPD) pattern comprising three or more peaksat 4.6, 9.2, 15.8, 17.8, 18.3, 19.2, 19.9, 22.4, 25.5 or 29.1 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the present invention provides a crystalline FormIII of Compound I, and solvates or hydrates thereof, characterized by anX-ray powder diffraction (XRPD) pattern having three or more peaks at5.0, 10.1, 16.9, 20.3, 21.5, 22.0, 23.9, or 25.2 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the present invention provides a crystalline FormIV of Compound I, and solvates or hydrates thereof, characterized by anX-ray powder diffraction (XRPD) pattern having peaks at 4.1, 18.1, 18.7,23.8, and 26.6 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is madeusing CuK_(α1) radiation.

In some embodiments, the present invention provides a crystalline FormIX of Compound I, and solvates or hydrates thereof, characterized by anX-ray powder diffraction (XRPD) pattern having three or more peaks at5.3, 9.8, 13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the present invention provides a crystalline Form Xof Compound I, and solvates or hydrates thereof, characterized by anX-ray powder diffraction (XRPD) pattern having three or more peaks at5.5, 9.4, 10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9, or 23.9 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the present invention provides a method ofpreparing a crystalline Form I of Compound I by forming a mixture ofCompound I, and a solvent including a C₁-C₃ alcohol and dichloromethane,under conditions suitable to prepare Form I.

In some embodiments, the present invention provides a method ofpreparing a crystalline Form II of Compound I by forming a mixture ofCompound I and chloroform, under conditions suitable to prepare Form II.

In some embodiments, the present invention provides a method ofpreparing a crystalline Form III of Compound I by heating a Form I ofCompound I to a temperature of from about 130° C. to about 190° C.,thereby forming Form III.

In some embodiments, the present invention provides a method ofpreparing a crystalline Form IV of Compound I by heating a Form II ofCompound I to a temperature of from about 90° C. to about 250° C.,thereby forming Form IV.

In some embodiments, the present invention provides a method ofpreparing a crystalline Form IX of Compound I by forming a mixturecomprising a Form I of Compound I, water and trifluoroethanol, underconditions suitable to prepare Form IX.

In some embodiments, the present invention provides a method ofpreparing a crystalline Form X of Compound I by forming a mixturecomprising a Form I of Compound I and chloroform, under conditionssuitable to prepare Form X.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction pattern of Compound I Form I.

FIG. 2 shows a table of X-ray powder diffraction peaks of Compound IForm I.

FIG. 3 shows a differential scanning calorimetry plot of Compound I FormI showing endotherms at about 133° C., about 170° C. and about 273° C.

FIG. 4 shows a variable temperature XRPD plot of Compound I Form Iconverting to Form III at about 138° C.

FIG. 5 shows an X-ray powder diffraction pattern of Compound I Form II.

FIG. 6 shows a table of X-ray powder diffraction peaks of Compound IForm II.

FIG. 7 shows a differential scanning calorimetry plot of Compound I FormII showing endotherms at about 98° C., about 253° C. and about 274° C.

FIG. 8 shows a variable temperature XRPD plot of Compound I Form IIconverting to Form IV at about 110° C., and then reverting to Form IIupon cooling to about 25° C.

FIG. 9 shows an X-ray powder diffraction pattern of Compound I Form III.

FIG. 10 shows a table of X-ray powder diffraction peaks of Compound IForm III.

FIG. 11 shows a differential scanning calorimetry plot of Compound IForm III showing endotherms at about 181 and about 271° C.

FIG. 12 shows a variable temperature XRPD plot of Compound I Form IIIfrom about 150° C. to about 25° C., and that Compound I remains as FormIII.

FIG. 13 shows an X-ray powder diffraction pattern of Compound I Form IV.

FIG. 14 shows a table of X-ray powder diffraction peaks of Compound IForm IV.

FIG. 15 shows an X-ray powder diffraction pattern of Compound I Forms I,II, III and IV.

FIG. 16 shows an X-ray powder diffraction pattern of Compound I Form V.

FIG. 17 shows an X-ray powder diffraction pattern of Compound I Form VI.

FIG. 18 shows an X-ray powder diffraction pattern of Compound I FormVII.

FIG. 19 shows an X-ray powder diffraction pattern of Compound I FormVIII.

FIG. 20 shows an X-ray powder diffraction pattern of Compound I Form IX.

FIG. 21 shows a table of X-ray powder diffraction peaks of Compound IForm IX.

FIG. 22 shows a differential scanning calorimetry plot of Compound IForm IX.

FIG. 23 shows an X-ray powder diffraction pattern of Compound I Form X.

FIG. 24 shows a table of X-ray powder diffraction peaks of Compound IForm X.

FIG. 25 shows a differential scanning calorimetry plot of Compound IForm X.

FIG. 26 shows an X-ray powder diffraction pattern of Compound I Form XI.

FIG. 27 shows a table of X-ray powder diffraction peaks of Compound IForm XI.

FIG. 28 shows an X-ray powder diffraction pattern of Compound I FormXII.

FIG. 29 shows a table of X-ray powder diffraction peaks of Compound IForm XII.

FIG. 30 shows a differential scanning calorimetry plot of Compound IForm XII.

FIG. 31 shows an X-ray powder diffraction pattern of Compound I FormXIII.

FIG. 32 shows a table of X-ray powder diffraction peaks of Compound IForm XIII.

FIG. 33 shows an X-ray powder diffraction pattern of Compound I FormXIV.

FIG. 34 shows a table of X-ray powder diffraction peaks of Compound IForm XIV.

DETAILED DESCRIPTION OF THE INVENTION I. General

The compound4-amino-2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one(Compound I) is a selective and potent inhibitor of toll-like receptor 7(TLR-7):

The present invention results from the surprising discoveries of thesolid forms of Compound I, advantages attributed to the forms asdescribed herein, and processes for making the solid forms. Crystallinematerials are generally more stable physically and chemically. Thesuperior stability of crystalline material may make them more suitableto be used in the final dosage form as shelf life of the product isdirectly correlated with stability. A crystallization step in APIprocessing also means an opportunity to upgrade the drug substancepurity by rejecting the impurities to the processing solvent.

II. Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

“Hydrate” refers to a complex formed by the combining of Compound I andwater. The term includes stoichiometric as well as non-stoichiometrichydrates.

“Solvate” refers to a complex formed by the combining of Compound I anda solvent.

“Desolvated” refers to a Compound I form that is a solvate as describedherein, and from which solvent molecules have been partially orcompletely removed. Desolvation techniques to produce desolvated formsinclude, without limitation, exposure of a Compound I Form (solvate) toa vacuum, subjecting the solvate to elevated temperature, exposing thesolvate to a stream of gas, such as air or nitrogen, or any combinationthereof. Thus, a desolvated Compound I form can be anhydrous, i.e.,completely without solvent molecules, or partially solvated whereinsolvent molecules are present in stoichiometric or non-stoichiometricamounts.

“Alcohol” refers to a solvent having a hydroxy group. Representativealcohols can have any suitable number of carbon atoms, such as C₁-C₆,and any suitable number of hydroxy groups, such as 1-3. Exemplaryalcohols include, but are not limited to, methanol, ethanol, n-propanol,i-propanol, etc.

“Therapeutically effective amount” refers to an amount that issufficient to effect treatment, as defined below, when administered to amammal in need of such treatment. The therapeutically effective amountwill vary depending upon the subject being treated, the weight and ageof the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

“Substantially free of other crystalline forms of Compound I” refers toa crystalline form of Compound I that contains less than 10% of othercrystalline forms of Compound I. For example, substantially free canrefer to a crystalline form of Compound I that contains less than 9, 8,7, 6, 5, 4, 3, 2, or 1% of other crystalline forms of Compound I.Preferably, substantially free refers to a crystalline form of CompoundI that contains less than 5% of other crystalline forms of Compound I.Preferably, substantially free refers to a crystalline form of CompoundI that contains less than 1% of other crystalline forms of Compound I.

III. Solid Forms of Compound I

The present invention provides solid forms of4-amino-2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one(Compound I; see U.S. Pat. Nos. 8,367,670 and 8,809,527), includingcrystalline and amorphous forms, as well as solvate and hydrate forms.In some embodiments, the present invention provides a crystalline formof Compound I having the structure:

and solvates or hydrates thereof.

Compound I can adopt a variety of solid forms, including, but notlimited to, Form I, Form II, Form III, and Form IV. Other forms includeForm V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, FormXII, Form XIII and Form XIV. Compound I can form a mixture of two ormore crystalline forms, or form a single crystalline form substantiallyfree of other crystalline forms.

Form I

In some embodiments, crystalline Form I of Compound I can becharacterized by an X-ray powder diffraction pattern having peaks at5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 and 26.8 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation,and a differential scanning calorimetry (DSC) plot having endotherms atabout 133° C., 170° C. and 273° C.

Form I of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least three, four, five, or more, peaks at 5.8,11.4, 11.6, 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 or 26.8 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form I of Compound I can be characterizedby an X-ray powder diffraction pattern having at least three peaks at5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 or 26.8 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. Insome embodiments, the crystalline Form I of Compound I can becharacterized by an X-ray powder diffraction pattern having at leastfour peaks at 5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 or26.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form I ofCompound I can be characterized by an XRPD pattern having at least fivepeaks at 5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 or 26.8degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation.

Form I of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine ormore, peaks at 5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 or26.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form I ofCompound I can be characterized by an X-ray powder diffraction patternhaving at least six peaks at 5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3,23.9, 26.0 or 26.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormI of Compound I can be characterized by an X-ray powder diffractionpattern having at least seven peaks at 5.8, 11.4, 11.6, 17.7, 20.1,20.9, 22.3, 23.9, 26.0 or 26.8 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form I of Compound I can be characterized by an XRPD patternhaving at least eight peaks at 5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3,23.9, 26.0 or 26.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormI of Compound I can be characterized by an X-ray powder diffractionpattern having at least nine peaks at 5.8, 11.4, 11.6, 17.7, 20.1, 20.9,22.3, 23.9, 26.0 or 26.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation.

In some embodiments, the crystalline Form I of Compound I can becharacterized by an X-ray powder diffraction (XRPD) pattern having threeor more peaks at 5.8, 11.4, 11.6, 17.7, 22.3, 23.9 or 26.0 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. Insome embodiments, the crystalline Form I of Compound I can becharacterized by an XRPD pattern having peaks at 5.8, 11.4, and 11.6degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form I of Compound I canbe characterized by an X-ray powder diffraction (XRPD) pattern furthercomprising one or more peaks at 17.7, 22.3, 23.9 or 26.0 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. Insome embodiments, the crystalline Form I of Compound I can becharacterized by an X-ray powder diffraction (XRPD) pattern furthercomprising two or more peaks at 17.7, 22.3, 23.9 or 26.0 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. Insome embodiments, the crystalline Form I of Compound I can becharacterized by an X-ray powder diffraction (XRPD) pattern furthercomprising three or more peaks at 17.7, 22.3, 23.9 or 26.0 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form I of Compound I can becharacterized by an XRPD pattern having peaks at 5.8, 11.6, 22.3, and23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form I ofCompound I can be characterized by an XRPD pattern having peaks at 5.8,11.6, 17.7, 22.3, 23.9, 26.0 and 26.8 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form I of Compound I can be characterized by an XRPDpattern having peaks at 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 and 26.8degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation.

In some embodiments, the crystalline Form I of Compound I can becharacterized by an XRPD pattern having peaks at 5.8, 11.4, 11.6, 17.7,20.1, 20.9, 22.3, 23.9, 26.0 and 26.8 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form I of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 1. In someembodiments, the crystalline Form I of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form I of Compound I can be substantially free of Form II,Form III and Form IV. In some embodiments, the crystalline Form I ofCompound I can also be substantially free of Form V, Form VI, Form VII,Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII and Form XIV.

Form I of Compound I can be characterized by a differential scanningcalorimetry (DSC) plot having at least one or more endotherms at about133° C., about 170° C., or about 273° C. In some embodiments, thecrystalline Form I of Compound I can be characterized by one or moredifferential scanning calorimetry (DSC) endotherms at about 133, 170, orabout 273° C. In some embodiments, the crystalline Form I of Compound Ican be characterized by one or more differential scanning calorimetry(DSC) endotherms at about 133° C. or about 170° C. In some embodiments,the crystalline Form I of Compound I can be characterized by DSCendotherms at about 133° C. and about 170° C. In some embodiments, thecrystalline Form I of Compound I can be characterized by one or moredifferential scanning calorimetry (DSC) endotherms at about 133, 170,and about 273° C.

In some embodiments, the crystalline Form I of Compound I can becharacterized by an XRPD pattern having peaks at 5.8, 11.4, 11.6, 17.7,20.1, 20.9, 22.3, 23.9, 26.0 and 26.8 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation, and one or more DSCendotherms at about 133° C. and about 170° C.

Form II

Form II of Compound I can be characterized by an XRPD pattern having atleast three, four, five, or more, peaks 4.6, 9.2, 15.8, 17.8, 18.3,19.2, 19.9, 22.4, 25.5 or 29.1 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form II of Compound I can be characterized by an XRPDpattern having at least three peaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2,19.9, 22.4, 25.5 or 29.1 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm II of Compound I can be characterized by an XRPD pattern having atleast four peaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2, 19.9, 22.4, 25.5or 29.1 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form II ofCompound I can be characterized by an XRPD pattern having at least fivepeaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2, 19.9, 22.4, 25.5 or 29.1degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation.

Form II of Compound I can also be characterized by an XRPD patternhaving at least six, seven, eight, nine, or more, peaks 4.6, 9.2, 15.8,17.8, 18.3, 19.2, 19.9, 22.4, 25.5 or 29.1 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form II of Compound I can be characterized by an XRPDpattern having at least six peaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2,19.9, 22.4, 25.5 or 29.1 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm II of Compound I can be characterized by an XRPD pattern having atleast seven peaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2, 19.9, 22.4, 25.5or 29.1 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form II ofCompound I can be characterized by an XRPD pattern having at least eightpeaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2, 19.9, 22.4, 25.5 or 29.1degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form II of Compound Ican be characterized by an XRPD pattern having at least nine peaks at4.6, 9.2, 15.8, 17.8, 18.3, 19.2, 19.9, 22.4, 25.5 or 29.1 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form II of Compound I can becharacterized by an X-ray powder diffraction (XRPD) pattern having threeor more peaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2, 19.9, 22.4, 25.5 or29.1 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form II ofCompound I can be characterized by an XRPD pattern having peaks at 4.6,18.3, 19.9, 22.4 and 25.5 degrees 2θ (t 0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form II of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern further comprising one or more peaksat 9.2, 15.8, 17.8, 19.2, or 29.1 degrees 2θ (±0.2 degrees 2θ), whereinthe XRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form II of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern further comprising two or more peaksat 9.2, 15.8, 17.8, 19.2, or 29.1 degrees 2θ (±0.2 degrees 2θ), whereinthe XRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form II of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern further comprising three or more peaksat 9.2, 15.8, 17.8, 19.2, or 29.1 degrees 2θ (t 0.2 degrees 2θ), whereinthe XRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form II of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern further comprising four or more peaksat 9.2, 15.8, 17.8, 19.2, or 29.1 degrees 2θ (±0.2 degrees 2θ), whereinthe XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form II of Compound I can becharacterized by an XRPD pattern having peaks at 4.6, 9.2, 15.8, 17.8,18.3, 19.2, 19.9, 22.4, 25.5 and 29.1 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form II of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 5. In someembodiments, the crystalline Form II of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form II of Compound I can be substantially free of Form I,Form III and Form IV. In some embodiments, the crystalline Form II ofCompound I can also be substantially free of Form V, Form VI, Form VII,Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII and Form XIV.

Form II of Compound I can be characterized by a differential scanningcalorimetry (DSC) plot having at least one or more endotherms at about98, about 253° C., or about 273° C. In some embodiments, the crystallineForm II of Compound I can be characterized by one or more differentialscanning calorimetry (DSC) endotherms at about 98, 253, or about 273° C.In some embodiments, the crystalline Form II of Compound I can becharacterized by one or more differential scanning calorimetry (DSC)endotherms at about 98 or about 253° C. In some embodiments, thecrystalline Form II of Compound I can be characterized by DSC endothermsat about 98° C. and about 253° C. In some embodiments, the crystallineForm II of Compound I can be characterized by one or more differentialscanning calorimetry (DSC) endotherms at about 98, 253, and about 273°C.

In some embodiments, the crystalline Form II of Compound I can becharacterized by an XRPD pattern having peaks at 4.6, 9.2, 15.8, 17.8,18.3, 19.2, 19.9, 22.4, 25.5 and 29.1 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation, and DSC endotherms atabout 98 and about 253° C.

Form III

Form III of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least three, four, five, or more,peaks at 5.0, 10.1, 15.2, 16.9, 20.3, 21.5, 22.0, 23.9, 25.2 or 29.4degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form III of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least three peaks at 5.0, 10.1, 15.2, 16.9, 20.3, 21.5, 22.0,23.9, 25.2 or 29.4 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormIII of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least four peaks at 5.0, 10.1, 15.2, 16.9,20.3, 21.5, 22.0, 23.9, 25.2 or 29.4 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form III of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having at least five peaks at 5.0,10.1, 15.2, 16.9, 20.3, 21.5, 22.0, 23.9, 25.2 or 29.4 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

Form III of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine, ormore, peaks at 5.0, 10.1, 15.2, 16.9, 20.3, 21.5, 22.0, 23.9, 25.2 or29.4 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form III ofCompound I can be characterized by an X-ray powder diffraction (XRPD)pattern having at least six peaks at 5.0, 10.1, 15.2, 16.9, 20.3, 21.5,22.0, 23.9, 25.2 or 29.4 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm III of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least seven peaks at 5.0, 10.1,15.2, 16.9, 20.3, 21.5, 22.0, 23.9, 25.2 or 29.4 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form III of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having at least eightpeaks at 5.0, 10.1, 15.2, 16.9, 20.3, 21.5, 22.0, 23.9, 25.2 or 29.4degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form III of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least nine peaks at 5.0, 10.1, 15.2, 16.9, 20.3, 21.5, 22.0,23.9, 25.2 or 29.4 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation.

In some embodiments, the crystalline Form III of Compound I can becharacterized by an XRPD pattern having three or more peaks at 5.0,10.1, 16.9, 20.3, 21.5, 22.0, 23.9 or 25.2 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form III of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having peaks at 5.0, 21.5, and 22.0degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form III of Compound Ican be characterized by an XRPD pattern further comprising one or morepeaks at 10.1, 16.9, 20.3, 23.9 or 25.2 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form III of Compound I can be characterized by an XRPDpattern further comprising two or more peaks at 10.1, 16.9, 20.3, 23.9or 25.2 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form III ofCompound I can be characterized by an XRPD pattern further comprisingthree or more peaks at 10.1, 16.9, 20.3, 23.9 or 25.2 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form III of Compound I can be characterizedby an XRPD pattern further comprising four or more peaks at 10.1, 16.9,20.3, 23.9 or 25.2 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation.

In some embodiments, the crystalline Form III of Compound I can becharacterized by an XRPD pattern having peaks at 5.0, 10.1, 15.2, 16.9,20.3, 21.5, 22.0, 23.9, 25.2 and 29.4 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form III of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 9. In someembodiments, the crystalline Form III of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form III of Compound I can be substantially free of Form I,Form II and Form IV. In some embodiments, the crystalline Form III ofCompound I can also be substantially free of Form V, Form VI, Form VII,Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII and Form XIV.

Form III of Compound I can be characterized by a differential scanningcalorimetry (DSC) plot having at least one or more endotherms at about181° C. or about 272° C. In some embodiments, the crystalline Form IIIof Compound I can be characterized by a differential scanningcalorimetry (DSC) endotherm at about 181° C. or about 272° C. In someembodiments, the crystalline Form III of Compound I can be characterizedby a differential scanning calorimetry (DSC) endotherm at about 181° C.In some embodiments, the crystalline Form II of Compound I can becharacterized by a differential scanning calorimetry (DSC) endotherm atabout 181° C. and about 272° C.

In some embodiments, the crystalline Form III of Compound I can becharacterized by an XRPD pattern having peaks at 5.0, 10.1, 15.2, 16.9,20.3, 21.5, 22.0, 23.9, 25.2 and 29.4 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation, and a DSC endothermat about 181° C.

Form IV

Form IV of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least three, four, five, or more,peaks at 4.1, 8.8, 16.8, 18.1, 18.7, 19.7, 21.1, 21.4, 23.8, or 26.6degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form IV of Compound Ican be can be characterized by an X-ray powder diffraction (XRPD)pattern having at least three peaks at 4.1, 8.8, 16.8, 18.1, 18.7, 19.7,21.1, 21.4, 23.8, or 26.6 degrees 2θ (0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm IV of Compound I can be can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least four peaks at 4.1, 8.8, 16.8,18.1, 18.7, 19.7, 21.1, 21.4, 23.8, or 26.6 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form IV of Compound I can be can becharacterized by an X-ray powder diffraction (XRPD) pattern having atleast five peaks at 4.1, 8.8, 16.8, 18.1, 18.7, 19.7, 21.1, 21.4, 23.8,or 26.6 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation.

Form IV of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine, ormore, peaks at 4.1, 8.8, 16.8, 18.1, 18.7, 19.7, 21.1, 21.4, 23.8, or26.6 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form IV ofCompound I can be can be characterized by an X-ray powder diffraction(XRPD) pattern having at least six peaks at 4.1, 8.8, 16.8, 18.1, 18.7,19.7, 21.1, 21.4, 23.8, or 26.6 degrees 2θ (±0.2 degrees 2θ), whereinthe XRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form IV of Compound I can be can be characterized by anX-ray powder diffraction (XRPD) pattern having at least seven peaks at4.1, 8.8, 16.8, 18.1, 18.7, 19.7, 21.1, 21.4, 23.8, or 26.6 degrees 2θ(t 0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.In some embodiments, the crystalline Form IV of Compound I can be can becharacterized by an X-ray powder diffraction (XRPD) pattern having atleast eight peaks at 4.1, 8.8, 16.8, 18.1, 18.7, 19.7, 21.1, 21.4, 23.8,or 26.6 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form IV ofCompound I can be can be characterized by an X-ray powder diffraction(XRPD) pattern having at least nine peaks at 4.1, 8.8, 16.8, 18.1, 18.7,19.7, 21.1, 21.4, 23.8, or 26.6 degrees 2θ (±0.2 degrees 2θ), whereinthe XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form IV of Compound I can becharacterized by an XRPD pattern having three or more peaks at 4.1,18.1, 18.7, 23.8, and 26.6 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form IV of Compound I can be characterized by an XRPDpattern further comprising one or more peaks at 8.8, 16.8, 19.7, 21.1,or 21.4 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form IV ofCompound I can be characterized by an XRPD pattern further comprisingtwo or more peaks at 8.8, 16.8, 19.7, 21.1, or 21.4 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form IV of Compound I can be characterizedby an XRPD pattern further comprising three or more peaks at 8.8, 16.8,19.7, 21.1, or 21.4 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormIV of Compound I can be characterized by an XRPD pattern furthercomprising four or more peaks at 8.8, 16.8, 19.7, 21.1, or 21.4 degrees2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form IV of Compound I can becharacterized by an XRPD pattern having peaks at 4.1, 8.8, 16.8, 18.1,18.7, 19.7, 21.1, 21.4, 23.8, and 26.6 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form IV of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 13. In someembodiments, the crystalline Form IV of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form IV of Compound I can be substantially free of Form I.Form II and Form III. In some embodiments, the crystalline Form IV ofCompound I can also be substantially free of Form V, Form VI, Form VII,Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII and Form XIV.

Forms V to VIII

Form V of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern substantially in accordance with that of FIG. 16. Form Vcan be any suitable solvate or hydrate form. In some embodiments, Form Vof Compound I can be a solvate with hexafluoroisopropanol.

Form VI of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern substantially in accordance with that of FIG.17. Form VI can be any suitable solvate or hydrate form.

Form VII of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern substantially in accordance with that of FIG.18. Form VII can be any suitable solvate or hydrate form. In someembodiments, Form VII of Compound I can be a solvate withtrifluoroethanol.

Form VIII of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern substantially in accordance with that of FIG.19. Form VIII can be any suitable solvate or hydrate form, such as ahemihydrate.

In some embodiments, the crystalline Form V of Compound I can besubstantially free of Form I, Form II, Form III, Form IV, Form VI, FormVII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII and FormXIV. In some embodiments, the crystalline Form VI of Compound I can besubstantially free of Form I, Form II, Form III, Form IV, Form V, FormVii, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII and FormXIV. In some embodiments, the crystalline Form VII of Compound I can besubstantially free of Form I, Form II, Form III, Form IV, Form V, FormVI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII and FormXIV. In some embodiments, the crystalline Form VIII of Compound I can besubstantially free of Form I, Form II, Form III, Form IV, Form V, FormVI, Form VII, Form IX, Form X, Form XI. Form XII. Form XIII and FormXIV.

Form IX

Form IX of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least three, four, five, or more,peaks at 5.3, 9.8, 13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form IX of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least three peaks at 5.3, 9.8, 13.1, 15.6, 17.0, 19.6, 20.0,20.7, 21.9 or 24.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormIX of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least four peaks at 5.3, 9.8, 13.1, 15.6, 17.0,19.6, 20.0, 20.7, 21.9 or 24.9 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form IX of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having at least five peaks at 5.3,9.8, 13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

Form IX of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine, ormore, peaks at 5.3, 9.8, 13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 or24.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form IX ofCompound I can be characterized by an X-ray powder diffraction (XRPD)pattern having at least six peaks at 5.3, 9.8, 13.1, 15.6, 17.0, 19.6,20.0, 20.7, 21.9 or 24.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm IX of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least seven peaks at 5.3, 9.8,13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form IX of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having at least eightpeaks at 5.3, 9.8, 13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form IX of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least nine peaks at 5.3, 9.8, 13.1, 15.6, 17.0, 19.6, 20.0,20.7, 21.9 or 24.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation.

In some embodiments, the crystalline Form IX of Compound I can becharacterized by an XRPD pattern having three or more peaks at 5.3, 9.8,13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form IX of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having peaks at 5.3, 9.8,and 15.6 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form IX ofCompound I can be characterized by an XRPD pattern further comprisingone or more peaks at 13.1, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9 degrees2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.In some embodiments, the crystalline Form IX of Compound I can becharacterized by an XRPD pattern further comprising two or more peaks at13.1, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form IX of Compound I can be characterized by an XRPDpattern further comprising three or more peaks at 13.1, 17.0, 19.6,20.0, 20.7, 21.9 or 24.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm IX of Compound I can be characterized by an XRPD pattern furthercomprising four or more peaks at 13.1, 17.0, 19.6, 20.0, 20.7, 21.9 or24.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form IX ofCompound I can be characterized by an XRPD pattern further comprisingfive or more peaks at 13.1, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9 degrees2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.In some embodiments, the crystalline Form IX of Compound I can becharacterized by an XRPD pattern further comprising six or more peaks at13.1, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form IX of Compound I can becharacterized by an XRPD pattern having peaks at 5.3, 9.8, 13.1, 15.6,17.0, 19.6, 20.0, 20.7, 21.9 and 24.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form IX of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 20. In someembodiments, the crystalline Form IX of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form IX of Compound I can be substantially free of Form I,Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, FormX, Form XI, Form XII, Form XIII and Form XIV.

Form IX of Compound I can be characterized by a differential scanningcalorimetry (DSC) plot having at least one or more endotherm at about57, 101, 141, 173, or about 266° C. In some embodiments, the crystallineForm IX of Compound I can be characterized by a differential scanningcalorimetry (DSC) endotherm at about 57, 101, 141, 173, or about 266° C.In some embodiments, the crystalline Form IX of Compound I can becharacterized by a differential scanning calorimetry (DSC) endotherm atabout 141 or about 173° C. In some embodiments, the crystalline Form IXof Compound I can be characterized by a differential scanningcalorimetry (DSC) endotherm at about 141 and about 173° C. In someembodiments, the crystalline Form IX of Compound I can be characterizedby a differential scanning calorimetry (DSC) endotherm at about 173 andabout 266° C. In some embodiments, the crystalline Form IX of Compound Ican be characterized by a differential scanning calorimetry (DSC)endotherm at about 173° C. In some embodiments, the crystalline Form IXof Compound I can be characterized by a differential scanningcalorimetry (DSC) endotherm at about 57, 101, 141, 173, and about 266°C.

In some embodiments, the crystalline Form IX of Compound I can becharacterized by an XRPD pattern having peaks at 5.3, 9.8, 13.1, 15.6,17.0, 19.6, 20.0, 20.7, 21.9 and 24.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation, and a DSC endothermat about 173° C.

The crystalline Form IX of Compound I can also have a solvate or hydrateform. In some embodiments, the crystalline Form IX of Compound I can bea hydrate.

Form X

Form X of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least three, four, five, or more, peaks at 5.5,9.4, 10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9, or 23.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form X of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having at least threepeaks at 5.5, 9.4, 10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9, or 23.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form X of Compound I canbe characterized by an X-ray powder diffraction (XRPD) pattern having atleast four peaks at 5.5, 9.4, 10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9,or 23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form X ofCompound I can be characterized by an X-ray powder diffraction (XRPD)pattern having at least five peaks at 5.5, 9.4, 10.8, 1.1.9, 12.9, 14.4,16.0, 19.0, 21.9, or 23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation.

Form X of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine, ormore, peaks at 5.5, 9.4, 10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9, or23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form X ofCompound I can be characterized by an X-ray powder diffraction (XRPD)pattern having at least six peaks at 5.5, 9.4, 10.8, 11.9, 12.9, 14.4,16.0, 19.0, 21.9, or 23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm X of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least seven peaks at 5.5, 9.4, 10.8, 11.9,12.9, 14.4, 16.0, 19.0, 21.9, or 23.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form X of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having at least eight peaks at 5.5,9.4, 10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9, or 23.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form X of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having at least nine peaksat 5.5, 9.4, 10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9, or 23.9 degrees2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form X of Compound I can becharacterized by an XRPD pattern having three or more peaks at 5.5, 9.4,10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9, or 23.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form X of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having peaks at 5.5, 10.8and 16.0 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form X ofCompound I can be characterized by an XRPD pattern further comprisingone or more peaks at 9.4, 11.9, 12.9, 14.4, 19.0, 21.9, or 23.9 degrees2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.In some embodiments, the crystalline Form X of Compound I can becharacterized by an XRPD pattern further comprising two or more peaks at9.4, 11.9, 12.9, 14.4, 19.0, 21.9, or 23.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form X of Compound I can be characterized by an XRPDpattern further comprising three or more peaks at 9.4, 11.9, 12.9, 14.4,19.0, 21.9, or 23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormX of Compound I can be characterized by an XRPD pattern furthercomprising four or more peaks at 9.4, 11.9, 12.9, 14.4, 19.0, 21.9, or23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form X ofCompound I can be characterized by an XRPD pattern further comprisingfive or more peaks at 9.4, 1.1.9, 12.9, 14.4, 19.0, 21.9, or 23.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form X of Compound I canbe characterized by an XRPD pattern further comprising six or more peaksat 9.4, 11.9, 12.9, 14.4, 19.0, 21.9, or 23.9 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form X of Compound I can becharacterized by an XRPD pattern having peaks at 5.5, 9.4, 10.8, 11.9,12.9, 14.4, 16.0, 19.0, 21.9, or 23.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form X of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 23. In someembodiments, the crystalline Form X of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form X of Compound I can be substantially free of Form I,Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, FormIX, Form XI, Form XII, Form XIII and Form XIV.

Form X of Compound I can be characterized by a differential scanningcalorimetry (DSC) plot having at least one endotherm at about 142° C. orabout 274° C. In some embodiments, the crystalline Form X of Compound Ican be characterized by a differential scanning calorimetry (DSC)endotherm at about 142 or about 274° C. In some embodiments, thecrystalline Form X of Compound I can be characterized by a differentialscanning calorimetry (DSC) endotherm at about 142° C. In someembodiments, the crystalline Form X of Compound I can be characterizedby a differential scanning calorimetry (DSC) endotherm at about 142 andabout 274° C.

In some embodiments, the crystalline Form X of Compound I can becharacterized by an XRPD pattern having peaks at 5.5, 9.4, 10.8, 11.9,12.9, 14.4, 16.0, 19.0, 21.9, and 23.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation, and a DSC endothermat about 142° C.

Form XI

Form XI of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least three, four, five, or more,peaks at 7.7, 8.4, 10.7, 17.1, 17.8, 19.3, 19.5, 21.4, 23.0 or 23.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XI of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least three peaks at 7.7, 8.4, 10.7, 17.1, 17.8, 19.3, 19.5,21.4, 23.0 or 23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormXI of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least four peaks at 7.7, 8.4, 10.7, 17.1, 17.8,19.3, 19.5, 21.4, 23.0 or 23.9 degrees 2θ (t 0.2 degrees 2θ), whereinthe XRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form XI of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having at least five peaks at 7.7,8.4, 10.7, 17.1, 17.8, 19.3, 19.5, 21.4, 23.0 or 23.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

Form XI of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine, ormore, peaks at 7.7, 8.4, 10.7, 17.1, 17.8, 19.3, 19.5, 21.4, 23.0 or23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form XI ofCompound I can be characterized by an X-ray powder diffraction (XRPD)pattern having at least six peaks at 7.7, 8.4, 10.7, 17.1, 17.8, 19.3,19.5, 21.4, 23.0 or 23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm XI of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least seven peaks at 7.7, 8.4,10.7, 17.1, 17.8, 19.3, 19.5, 21.4, 23.0 or 23.9 degrees 2θ (0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XI of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having at least eightpeaks at 7.7, 8.4, 10.7, 17.1, 17.8, 19.3, 19.5, 21.4, 23.0 or 23.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XI of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least nine peaks at 7.7, 8.4, 10.7, 17.1, 17.8, 19.3, 19.5,21.4, 23.0 or 23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation.

In some embodiments, the crystalline Form XI of Compound I can becharacterized by an XRPD pattern having three or more peaks at 7.7, 8.4,10.7, 17.1, 17.8, 19.3, 19.5, 21.4, 23.0 or 23.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XI of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having peaks at 7.7, 17.1and 19.5 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form XI ofCompound I can be characterized by an XRPD pattern further comprisingone or more peaks at 8.4, 10.7, 17.8, 19.3, 21.4, 23.0 or 23.9 degrees2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.In some embodiments, the crystalline Form XI of Compound I can becharacterized by an XRPD pattern further comprising two or more peaks at8.4, 10.7, 17.8, 19.3, 21.4, 23.0 or 23.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form XI of Compound I can be characterized by an XRPDpattern further comprising three or more peaks at 8.4, 10.7, 17.8, 19.3,21.4, 23.0 or 23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormXI of Compound I can be characterized by an XRPD pattern furthercomprising four or more peaks at 8.4, 10.7, 17.8, 19.3, 21.4, 23.0 or23.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form XI ofCompound I can be characterized by an XRPD pattern further comprisingfive or more peaks at 8.4, 10.7, 17.8, 19.3, 21.4, 23.0 or 23.9 degrees2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.In some embodiments, the crystalline Form XI of Compound I can becharacterized by an XRPD pattern further comprising six or more peaks at8.4, 10.7, 17.8, 19.3, 21.4, 23.0 or 23.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form XI of Compound I can becharacterized by an XRPD pattern having peaks at 7.7, 8.4, 10.7, 17.1,17.8, 19.3, 19.5, 21.4, 23.0 and 23.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form XI of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 26. In someembodiments, the crystalline Form XI of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form XI of Compound I can be substantially free of Form I,Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, FormIX, Form X, Form XII, Form XIII, and Form XIV.

The crystalline Form XI of Compound I can also have a solvate or hydrateform. In some embodiments, the crystalline Form XI of Compound I can bea solvate with hexafluoroisopropanol (HFIPA).

Form XII

Form XII of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least three, four, five, or more,peaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7, 20.3, 21.1, 21.9, or 25.8degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XII of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least three peaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7, 20.3,21.1, 21.9, or 25.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormXII of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least four peaks at 6.0, 9.0, 10.9, 13.7, 17.1,18.7, 20.3, 21.1, 21.9 or 25.8 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form XII of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having at least five peaks at 6.0,9.0, 10.9, 13.7, 17.1, 18.7, 20.3, 21.1, 21.9, or 25.8 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

Form XII of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine, ormore, peaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7, 20.3, 21.1, 21.9, or25.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form XII ofCompound I can be characterized by an X-ray powder diffraction (XRPD)pattern having at least six peaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7,20.3, 21.1, 21.9, or 25.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm XII of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least seven peaks at 6.0, 9.0,10.9, 13.7, 17.1, 18.7, 20.3, 21.1, 21.9, or 25.8 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XII of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having at least eightpeaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7, 20.3, 21.1, 21.9, or 25.8degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XII of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least nine peaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7, 20.3,21.1, 21.9, or 25.8 degrees 2θ (f 0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation.

In some embodiments, the crystalline Form XII of Compound I can becharacterized by an XRPD pattern having three or more peaks at 6.0, 9.0,10.9, 13.7, 17.1, 18.7, 20.3, 21.1, 21.9, or 25.8 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XII of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having peaks at 20.3, 21.1and 21.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form XII ofCompound I can be characterized by an XRPD pattern further comprising atleast one or more peaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7, or 25.8degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XII of Compound Ican be characterized by an XRPD pattern further comprising at least twoor more peaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7, or 25.8 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. Insome embodiments, the crystalline Form XII of Compound I can becharacterized by an XRPD pattern further comprising at least three ormore peaks at 6.0, 9.0, 10.9, 13.7, 17.1, 18.7, or 25.8 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XII of Compound I can be characterizedby an XRPD pattern further comprising at least four or more peaks at6.0, 9.0, 10.9, 13.7, 17.1, 18.7, or 25.8 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form XII of Compound I can be characterized by an XRPDpattern further comprising at least five or more peaks at 6.0, 9.0,10.9, 13.7, 17.1, 18.7, or 25.8 degrees 2θ (±0.2 degrees 2θ), whereinthe XRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form XII of Compound I can be characterized by an XRPDpattern further comprising at least six or more peaks at 6.0, 9.0, 10.9,13.7, 17.1, 18.7, or 25.8 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation.

In some embodiments, the crystalline Form XII of Compound I can becharacterized by an XRPD pattern having peaks at 6.0, 9.0, 10.9, 13.7,17.1, 18.7, 20.3, 21.1, 21.9, and 25.8 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form XII of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 28. In someembodiments, the crystalline Form XII of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form XII of Compound I can be substantially free of Form I,Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, FormIX, Form X, Form XI, Form XIII, and Form XIV.

Form XII of Compound I can be characterized by a differential scanningcalorimetry (DSC) plot having an endotherm at about 94° C., 112° C.,140° C. or about 174° C. In some embodiments, the crystalline Form XIIof Compound I can be characterized by a differential scanningcalorimetry (DSC) endotherm at about 94° C., 112° C., 140° C. or about174° C. In some embodiments, the crystalline Form XII of Compound I canbe characterized by a differential scanning calorimetry (DSC) endothermat about 174° C. In some embodiments, the crystalline Form XII ofCompound I can be characterized by a differential scanning calorimetry(DSC) endotherm at about 94° C., 112° C., 140° C. and about 174° C.

In some embodiments, the crystalline Form XII of Compound I can becharacterized by an XRPD pattern having peaks at 6.0, 9.0, 10.9, 13.7,17.1, 18.7, 20.3, 21.1, 21.9, or 25.8 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation, and a DSC endothermat about 174° C.

The crystalline Form XII of Compound I can also have a solvate orhydrate form. In some embodiments, the crystalline Form XII of CompoundI can be a solvate with trifluoroethanol (TFE).

Form XIII

Form XIII of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least three, four, five, or more,peaks at 4.6, 8.9, 9.2, 13.8, 15.8, 16.0, 18.4, 20.0, 23.1 or 26.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XIII of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least three peaks at 4.6, 8.9, 9.2, 13.8, 15.8, 16.0, 18.4,20.0, 23.1 or 26.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormXIII of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least four peaks at 4.6, 8.9, 9.2, 13.8, 15.8,16.0, 18.4, 20.0, 23.1 or 26.9 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form XIII of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having at least five peaks at 4.6,8.9, 9.2, 13.8, 15.8, 16.0, 18.4, 20.0, 23.1 or 26.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

Form XIII of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine, ormore, peaks at 4.6, 8.9, 9.2, 13.8, 15.8, 16.0, 18.4, 20.0, 23.1 or 26.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XIII of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least six peaks at 4.6, 8.9, 9.2, 13.8, 15.8, 16.0, 18.4,20.0, 23.1 or 26.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormXIII of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least seven peaks at 4.6, 8.9, 9.2, 13.8, 15.8,16.0, 18.4, 20.0, 23.1 or 26.9 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form XIII of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having at least eight peaks at 4.6,8.9, 9.2, 13.8, 15.8, 16.0, 18.4, 20.0, 23.1 or 26.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XIII of Compound I can becharacterized by an X-ray powder diffraction (XRPD) pattern having atleast nine peaks at 4.6, 8.9, 9.2, 13.8, 15.8, 16.0, 18.4, 20.0, 23.1 or26.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation.

In some embodiments, the crystalline Form XIII of Compound I can becharacterized by an XRPD pattern having three or more peaks at 4.6, 8.9,9.2, 13.8, 15.8, 16.0, 18.4, 20.0, 23.1 or 26.9 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XIII of Compound I can becharacterized by an X-ray powder diffraction (XRPD) pattern having peaksat 4.6, 9.2, 18.4 and 20.0 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form XIII of Compound I can be characterized by an XRPDpattern further comprising one or more peaks at 8.9, 13.8, 15.8, 16.0,23.1 or 26.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is madeusing CuK_(α1) radiation. In some embodiments, the crystalline Form XIIIof Compound I can be characterized by an XRPD pattern further comprisingtwo or more peaks at 8.9, 13.8, 15.8, 16.0, 23.1 or 26.9 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. Insome embodiments, the crystalline Form XIII of Compound I can becharacterized by an XRPD pattern further comprising three or more peaksat 8.9, 13.8, 15.8, 16.0, 23.1 or 26.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form XIII of Compound I can be characterized by an XRPDpattern further comprising four or more peaks at 8.9, 13.8, 15.8, 16.0,23.1 or 26.9 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is madeusing CuK_(α1) radiation. In some embodiments, the crystalline Form XIIIof Compound I can be characterized by an XRPD pattern further comprisingfive or more peaks at 8.9, 13.8, 15.8, 16.0, 23.1 or 26.9 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

In some embodiments, the crystalline Form XIII of Compound I can becharacterized by an XRPD pattern having peaks at 4.6, 8.9, 9.2, 13.8,15.8, 16.0, 18.4, 20.0, 23.1 or 26.9 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form XIII of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 31. In someembodiments, the crystalline Form XIII of Compound I can besubstantially free of other crystalline forms of Compound I. In someembodiments, the crystalline Form XIII of Compound I can besubstantially free of Form I, Form II, Form III, Form IV, Form V, FormVI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, and FormXIV.

Form XIV

Form XIV of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least three, four, five, or more,peaks at 7.1, 9.5, 10.6, 14.3, 16.8, 17.6, 22.0, 24.6, 24.9 or 26.2degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XIV of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least three peaks at 7.1, 9.5, 10.6, 14.3, 16.8, 17.6, 22.0,24.6, 24.9 or 26.2 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormXIV of Compound I can be characterized by an X-ray powder diffraction(XRPD) pattern having at least four peaks at 7.1, 9.5, 10.6, 14.3, 16.8,17.6, 22.0, 24.6, 24.9 or 26.2 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation. In some embodiments, thecrystalline Form XIV of Compound I can be characterized by an X-raypowder diffraction (XRPD) pattern having at least five peaks at 7.1,9.5, 10.6, 14.3, 16.8, 17.6, 22.0, 24.6, 24.9 or 26.2 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.

Form XIV of Compound I can also be characterized by an X-ray powderdiffraction (XRPD) pattern having at least six, seven, eight, nine, ormore, peaks at 7.1, 9.5, 10.6, 14.3, 16.8, 17.6, 22.0, 24.6, 24.9 or26.2 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation. In some embodiments, the crystalline Form XIV ofCompound I can be characterized by an X-ray powder diffraction (XRPD)pattern having at least six peaks at 7.1, 9.5, 10.6, 14.3, 16.8, 17.6,22.0, 24.6, 24.9 or 26.2 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation. In some embodiments, the crystallineForm XIV of Compound I can be characterized by an X-ray powderdiffraction (XRPD) pattern having at least seven peaks at 7.1, 9.5,10.6, 14.3, 16.8, 17.6, 22.0, 24.6, 24.9 or 26.2 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XIV of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having at least eightpeaks at 7.1, 9.5, 10.6, 14.3, 16.8, 17.6, 22.0, 24.6, 24.9 or 26.2degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XIV of Compound Ican be characterized by an X-ray powder diffraction (XRPD) patternhaving at least nine peaks at 7.1, 9.5, 10.6, 14.3, 16.8, 17.6, 22.0,24.6, 24.9 or 26.2 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation.

In some embodiments, the crystalline Form XIV of Compound I can becharacterized by an XRPD pattern having three or more peaks at 7.1, 9.5,10.6, 14.3, 16.8, 17.6, 22.0, 24.6, 24.9 or 26.2 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XIV of Compound I can be characterizedby an X-ray powder diffraction (XRPD) pattern having peaks at 7.1, 9.5,14.3 and 24.6 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is madeusing CuK_(α1) radiation. In some embodiments, the crystalline Form XIVof Compound I can be characterized by an XRPD pattern further comprisingone or more peaks at 10.6, 16.8, 17.6, 22.0, 24.9 or 26.2 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. Insome embodiments, the crystalline Form XIV of Compound I can becharacterized by an XRPD pattern further comprising two or more peaks at10.6, 16.8, 17.6, 22.0, 24.9 or 26.2 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form XIV of Compound I can be characterized by an XRPDpattern further comprising three or more peaks at 10.6, 16.8, 17.6,22.0, 24.9 or 26.2 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD ismade using CuK_(α1) radiation. In some embodiments, the crystalline FormXIV of Compound I can be characterized by an XRPD pattern furthercomprising four or more peaks at 10.6, 16.8, 17.6, 22.0, 24.9 or 26.2degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation. In some embodiments, the crystalline Form XIV of Compound Ican be characterized by an XRPD pattern further comprising five or morepeaks at 10.6, 16.8, 17.6, 22.0, 24.9 or 26.2 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation. In someembodiments, the crystalline Form XIV of Compound I can be characterizedby an XRPD pattern further comprising six or more peaks at 10.6, 16.8,17.6, 22.0, 24.9 or 26.2 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation.

In some embodiments, the crystalline Form XIV of Compound I can becharacterized by an XRPD pattern having peaks at 7.1, 9.5, 10.6, 14.3,16.8, 17.6, 22.0, 24.6, 24.9 and 26.2 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation. In some embodiments,the crystalline Form XIV of Compound I can be characterized by the XRPDpattern substantially in accordance with that of FIG. 28. In someembodiments, the crystalline Form XIV of Compound I can be substantiallyfree of other crystalline forms of Compound I. In some embodiments, thecrystalline Form XIV of Compound I can be substantially free of Form I,Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, FormIX, Form X, Form XI, Form XII, and Form XIII.

The crystalline Form XIV of Compound I can also have a solvate orhydrate form. In some embodiments, the crystalline Form XIV of CompoundI can be a solvate with trifluoroethanol (TFE). In some embodiments, thecrystalline Form XIV of Compound I can be a hydrate.

Any formula or structure given herein, including Compound I, is alsointended to represent unlabeled forms as well as isotopically labeledforms of the compounds. Isotopically labeled compounds have structuresdepicted by the Formulae given herein except that one or more atoms arereplaced by an atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into compounds of thedisclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as, but not limited to ²H(deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S,³⁶Cl and ¹²⁵I. Various isotopically labeled compounds of the presentdisclosure, for example those into which radioactive isotopes such as³H, ¹³C and ¹⁴C are incorporated. Such isotopically labeled compoundsmay be useful in metabolic studies, reaction kinetic studies, detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays or in radioactive treatment ofpatients.

The disclosure also includes Compound I in which from 1 to “n” hydrogensattached to a carbon atom is/are replaced by deuterium, in which n isthe number of hydrogens in the molecule. Such compounds exhibitincreased resistance to metabolism and are thus useful for increasingthe half-life of any Compound I when administered to a mammal. See, forexample, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogen atoms have beenreplaced by deuterium.

Deuterium labeled or substituted therapeutic compounds of the disclosuremay have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuteriun may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. An¹⁸F labeled compound may be useful for PET or SPECT studies.Isotopically labeled compounds of this disclosure and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., ²H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vive half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in Compound I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

IV. Methods of Preparing Solid Forms of Compound I

The solid forms of Compound I can be prepared by a variety of methods.For example, Compound I can be dissolved in a single solvent system andallowed to crystallize. Alternatively, Compound I can be crystallizedfrom a two-solvent system by dissolving Compound I in a solvent, andthen adding an anti-solvent to the mixture causing Compound I tocrystallize.

The solvent can be any solvent suitable to form a solution. Typicallythe solvent can be a polar solvent, which in some embodiments is aprotic solvent. Other suitable solvents include non-polar solvents.Suitable solvents include, but are not limited to, water, alkanes suchas heptanes, hexanes, and cyclohexane, petroleum ether, C₁-C₃ alcohols(methanol, ethanol, propanol, isopropanol), ethylene glycol andpolyethylene glycol such as PEG400, alkanoates such as ethyl acetate,propyl acetate, isopropyl acetate, and butyl acetate, acetonitrile,alkanones such as acetone, butanone, methyl ethyl ketone (MEK), methylpropyl ketone (MPK) and methyl iso-butyl ketone (MIBK), ethers such asdiethyl ether, methyl-t-butyl ether, tetrahydrofuran,methyl-tetrahydrofuran, 1,2-dimethoxy ethane and 1,4-dioxane, aromaticssuch as benzene and toluene, halogenated solvents such as methylenechloride, chloroform and carbon tetrachloride, dimethylsulfoxide (DMSO),and dimethylformamide (DMF). Suitable solvents also include, but are notlimited to halogenated C₁-C₃ alcohols (trifluoromethanol,trifluoroethanol (TFE), hexafluoroisopropanol (HFIPA)).

The methods of preparing crystalline forms of Compound I can beperformed under any suitable reaction conditions. For example, themethods of preparing the crystalline forms of Compound I can beperformed at any suitable temperature, such as, but not limited to,below room temperature, at room temperature, or above room temperature.In some embodiments, the temperature can be from about −78° C. to about100° C., or from about 0° C. to about 50° C., or from about 10° C. toabout 30° C. In some embodiments, the temperature can be the refluxtemperature of the particular solvent used in the method. In otherembodiments, crystalline forms of Compound I can be heated above about100° C. such that one crystalline form of Compound I forms a secondcrystalline form of Compound I.

The methods of preparing crystalline forms of Compound I can beperformed for any suitable time. For example, the time can be forminutes, hours or days. In some embodiments, the time can be severalhours, such as overnight. The methods of preparing crystalline forms ofCompound I can be also be performed at any suitable pressure. Forexample, the pressure can be below atmospheric pressure, at aboutatmospheric pressure, or above atmospheric pressure.

Form I

In some embodiments, the present invention provides a method ofpreparing a crystalline Form I of Compound I of the present invention,including forming a mixture of Compound I of the present invention, anda solvent, under conditions suitable to prepare Form I. Any suitablesolvent can be used in the method of preparing Compound I Form I. Insome embodiments, the solvent can be at least one of water, methanol,ethanol, isopropanol, methyl ethyl ketone, methyl iso-butyl ketone,acetonitrile, tetrahydrofuran, methyl-tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, 1,4-dioxane, or dichloromethane. In someembodiments, the solvent can be at least one of methanol, ethanol,isopropanol, or dichloromethane. In some embodiments, the solvent caninclude one of methanol, ethanol, or isopropanol. In some embodiments,the solvent can be at least one of methanol, ethanol, or isopropanol, incombination with dichloromethane. In some embodiments, the solvent canbe methanol and dichloromethane.

In some embodiments, the present invention provides a method ofpreparing a crystalline Form I of Compound I by forming a mixture ofCompound I, and a solvent including a C₁-C₃ alcohol and dichloromethane,under conditions suitable to prepare Form I. The C₁-C₃ alcohol can bemethanol, ethanol, propanol or isopropanol. In some embodiments, thesolvent includes one of methanol, ethanol or isopropanol. In someembodiments, the solvent includes methanol and dichloromethane. In someembodiments, the solvent includes ethanol and dichloromethane. In someembodiments, the solvent includes isopropanol and dichloromethane.

Any suitable ratio of the methanol and dichloromethane can be used. Forexample, the ratio of methanol and dichloromethane can be from 10:1 toabout 1:10 (volume/volume), including about 10:1, 9:1, 8:1, 7:1, 6:1,5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or about1:10 (volume/volume). In some embodiments, the ratio of methanol todichloromethane can be from about 1:1 to about 1:5 (volume/volume). Insome embodiments, the ratio of methanol to dichloromethane can be about1:2 (volume/volume).

The method of preparing Form I of Compound I can include a variety ofother steps. For example, the solvent can be evaporated, a seed crystalcan be added to the mixture, the mixture can be heated and cooled asingle time or repeatedly, etc. In some embodiments, the method ofpreparing Form I of Compound I also includes evaporating the solvent,thereby forming Form I. In some embodiments, the method of preparingForm I of Compound I includes forming a reaction mixture of Compound I,methanol and dichloromethane, wherein the ratio of methanol todichloromethane is 1:2 (volume/volume), and removing thedichloromethane, thereby forming crystalline Form I of Compound I.

Form II

The present invention also provides methods for preparing Compound IForm II. In some embodiments, the present invention provides a method ofpreparing a crystalline Form II of Compound I by forming a mixture ofCompound I and chloroform, under conditions suitable to prepare Form II.The conditions for preparing crystalline Form III of Compound I caninclude ambient temperature and pressure for a period of time of atleast 1 day. The period of time for preparing crystalline Form II ofCompound I can also be for at least 2, 3, 4, 5, or more days. In someembodiments, the method for preparing the crystalline Form II ofCompound I can be for about 5 days.

Form III

The present invention also provides methods for preparing Compound IForm III. In some embodiments, the present invention provides a methodof preparing a crystalline Form III of Compound I by heating a Form I ofCompound I to a temperature of from about 130° C. to about 190° C.,thereby forming Form III. In some embodiments, the method also includescooling Form III to room temperature.

Form IV

The present invention also provides methods for preparing Compound IForm IV. In some embodiments, the present invention provides a method ofpreparing a crystalline Form IV of Compound I by heating a Form II ofCompound I to a temperature of from about 90° C. to about 250° C.,thereby forming Form IV.

Form V

The present invention also provides methods for preparing Compound IForm V. In some embodiments, the present invention provides a method ofpreparing a crystalline Form V of Compound I by forming a mixture ofCompound I and hexafluoroisopropanol, and removing thehexafluoroisopropanol, under conditions suitable to prepare Form V. Thehexafluoroisopropanol can be removed under any suitable conditions suchas via vacuum, heating, or a combination of the two. Alternatively, FormV can be formed by combining a hot solution of Compound I with coldwater and isolating the subsequent solid.

Form VI

The present invention also provides methods for preparing Compound IForm VI. In some embodiments, the present invention provides a method ofpreparing a crystalline Form VI of Compound I by forming a mixture ofCompound I and trifluoroethanol, and removing the trifluoroethanol,under conditions suitable to prepare Form VI. The trifluoroethanol canbe removed under any suitable conditions such as via vacuum, heating, ora combination of the two.

Form VII

The present invention also provides methods for preparing Compound IForm VII. In some embodiments, the present invention provides a methodof preparing a crystalline Form VII of Compound I by forming a mixtureof Compound I and trifluoroethanol, and removing the trifluoroethanol,under conditions suitable to prepare Form VII. The trifluoroethanol canbe removed under any suitable conditions such as via vacuum, heating, ora combination of the two.

Form VIII

The present invention also provides methods for preparing Compound IForm VIII. In some embodiments, the present invention provides a methodof preparing a crystalline Form VIII of Compound I by exposing CompoundI Form V or Form VII to an atmosphere with a relative humidity greaterthan about 90%, under conditions suitable to prepare Form VIII. Therelative humidity can be any suitable humidity, such as greater thanabout 50%, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97,98 or greater than about 99%. In some embodiments, the relative humiditycan be greater than about 95%. In some embodiments, the relativehumidity can be about 97%.

Form IX

The present invention also provides methods for preparing Compound IForm IX. In some embodiments, the present invention provides a method ofpreparing a crystalline Form IX of Compound I by forming a mixture of aForm I of Compound I, water and trifluoroethanol, under conditionssuitable to prepare Form IX. Any suitable ratio of the trifluoroethanoland water can be used. For example, the ratio of trifluoroethanol towater can be from 10:1 to about 1:1 (volume/volume), including about10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or about 1:1(volume/volume). In some embodiments, the ratio of trifluoroethanol towater can be from about 10:1 to about 1:1 (volume/volume). In someembodiments, the ratio of trifluoroethanol to water can be about 5:1(volume/volume). The conditions for preparing crystalline Form IX ofCompound I can include ambient temperature and pressure for a period oftime of at least 1 day. The period of time for preparing crystallineForm IX of Compound I can also be for at least 2, 3, 4, 5, or more days.In some embodiments, the method for preparing the crystalline Form IX ofCompound I can be for about 5 days.

Form X

The present invention also provides methods for preparing Compound IForm X. In some embodiments, the present invention provides a method ofpreparing a crystalline Form X of Compound I by forming a mixture of aForm I of Compound I and chloroform, under conditions suitable toprepare Form X. The suitable conditions for preparing the crystallineForm X of Compound I can include ambient temperature and pressure.

Form XI

The present invention also provides methods for preparing Compound IForm XI. In some embodiments, the present invention provides a method ofpreparing a crystalline Form XI of Compound I by forming a mixture of aForm I of Compound I and hexafluoroisopropanol, under conditionssuitable to prepare Form XI.

Form XII

The present invention also provides methods for preparing Compound IForm XII. In some embodiments, the present invention provides a methodof preparing a crystalline Form XII of Compound I by forming a mixtureof a Form I of Compound I, water and trifluoroethanol, under conditionssuitable to prepare Form XII. Any suitable ratio of the trifluoroethanoland water can be used. For example, the ratio of trifluoroethanol towater can be from 20:1 to about 1:1 (volume/volume), including about20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 10:1, 9:1, 8:1,7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or about 1:1 (volume/volume). In someembodiments, the ratio of trifluoroethanol to water can be from about20:1 to about 1:1 (volume/volume). In some embodiments, the ratio oftrifluoroethanol to water can be from about 15:1 to about 5:1(volume/volume). In some embodiments, the ratio of trifluoroethanol towater can be about 10:1 (volume/volume).

Form XIII

The present invention also provides methods for preparing Compound IForm XIII. In some embodiments, the present invention provides a methodof preparing a crystalline Form XIII of Compound I by cooling Form II ofCompound I to less than 0° C., under conditions suitable to prepare FormXIII. Form II of Compound I can be cooled to any suitable temperatureless than 0° C., including, but not limited to, −5° C., −10, −15, −20,−25, −30, −40, −50, −60 and −70° C. In some embodiments, Form II ofCompound I can be cooled to about −10° C. to prepare Form XIII.

Form XIV

The present invention also provides methods for preparing Compound IForm XIV. In some embodiments, the present invention provides a methodof preparing a crystalline Form XIV of Compound I by drying Form XIIunder conditions suitable to prepare Form XIV. The drying can includeheating Form XII to a suitable temperature for a suitable period oftime, placing Form XII in a reduced atmosphere environment, or both. Forexample, Form XII can be heated to a temperature above room temperature,such as 30° C., 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, or 100° C.When Form XII is dried in a reduced atmosphere environment, the reducedatmosphere can have any suitable pressure less than 1 atmosphere, suchas 0.9 atm, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.01, 0.005,0.001 atm, or less. In some embodiments, preparing Form XIV includesdrying Form XII at a pressure less than 1 atmosphere. In someembodiments, preparing Form XIV includes heating Form XII. In someembodiments, preparing Form XIV including drying Form XII at a pressureless than 1 atmosphere, and heating Form XII at a temperature of about40° C.

The method of preparing crystalline Compound I can be carried out attemperatures generally from about 0° C. to the reflux temperature of thesolvent. In some embodiments, the temperature can be room temperature.Alternatively, Compound I, or one of the crystalline forms of CompoundI, can be heated in solid state form. For example, Compound I Form I canbe heated to a temperature of from about 130° C. to about 200° C., orfrom about 130° C. to about 150° C. Compound I Form II can be heated toa temperature of from about 90° C. to about 200° C.

When multiple solvents are used in the methods of the present invention,the ratio of solvents in the above methods can be any suitable ratiofrom about 1:1 to about 1:9, including about 1:2, 1:3, 1:4, 1:5, 1:6,1:7 and about 1:8 by volume. The range of solvent ratios is preferablyfrom about 1:1 to about 1:9, more preferably from about 1:2 to about1:7, even more preferably from about 1:2 to about 1:5 by volume.

The ratio of Compound I to solvent, can be any suitable ratio to promotecrystallization. For example, the Compound I to solvent ratio can befrom about 1:5 (weight/volume, or w/v) to about 1:50 (w/v), includingabout 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:20,1:25, 1:30, 1:35, 1:40 and about 1:45 (w/v). The Compound I to solventratio is preferably from about 1:10 to about 1:25 (w/v), more preferablyfrom about 1:10 to about 1:15 (w/v).

Crystallization can be induced by methods known in the art, for exampleby mechanical means such as scratching or rubbing the contact surface ofthe reaction vessel with e.g. a glass rod. Optionally the saturated orsupersaturated solution may be inoculated with seed crystals. Themixture for crystallizing Compound I can also contain a seed crystal ofcrystalline Compound I.

Isolation of the desired crystalline form can be accomplished byremoving the solvent and precipitating solvent from the crystals.Generally this is carried out by known methods, such as, filtration,suction filtration, decantation or centrifugation. Further isolation canbe achieved by removing any excess of the solvent(s) from thecrystalline form by methods known to the one skilled in the art as forexample application of a vacuum, and/or by heating.

V. Pharmaceutical Compositions

The solid forms of Compound I provided herein can be administered in theform of pharmaceutical compositions. This disclosure providespharmaceutical compositions that contain, as the active ingredient, oneor more of the solid forms of Compound I described or a pharmaceuticallyacceptable salt or ester thereof and one or more pharmaceuticallyacceptable excipients, carriers, including inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants. Thepharmaceutical compositions may be administered alone or in combinationwith other therapeutic agents (as indicated in the Combination Therapysection below). Such compositions are prepared in a manner well known inthe pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences,Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and ModernPharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes,Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously orally, topically, as an inhalant or via an impregnatedor coated device such as a stent, for example or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present disclosure maybe incorporated for administration by injection include aqueous or oilsuspensions or emulsions, with sesame oil, corn oil, cottonseed oil orpeanut oil, as well as elixirs, mannitol, dextrose or a sterile aqueoussolution and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present disclosure. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present disclosure in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the general methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of compounds inaccordance with the disclosure. Administration may be via capsule orenteric coated tablets or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions and sterilepackaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the disclosure can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present disclosure employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present disclosure incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile or on demand delivery ofpharmaceutical agents.

In some embodiments, the compositions are formulated in a unit dosageform. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).The compounds are generally administered in a pharmaceutically effectiveamount. In some embodiments, each dosage unit contains from 1 mg to 2 gof a compound described herein and for parenteral administration, insome embodiments, from 0.1 to 700 mg of a compound a compound describedherein. It will be understood, however, that the amount of the compoundactually administered usually will be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered and its relative activity, the age, weight and response ofthe individual patient, the severity of the patient's symptoms, and thelike.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present disclosure may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solventsor mixtures thereof and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in preferably pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent or intermittent positive pressure breathingmachine. Solution, suspension or powder compositions may beadministered, in some embodiments orally or nasally, from devices thatdeliver the formulation in an appropriate manner.

In one embodiment, this disclosure relates to a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient orcarrier and a therapeutically effective amount of the compound ofCompound I as described above or a pharmaceutically acceptable salt,ester, prodrug, stereoisomer or hydrate thereof.

VI. Methods of Use

The solid forms of Compound I described herein can be administered to asubject suffering from a viral infection such as, but not limited to,hepatitis B virus (HBV), hepatitis C virus (HCV), and humanimmuno-deficiency virus (HIV) in either single or multiple doses by anyof the accepted modes of administration known to those who are skilledin the art and as detailed above.

As used herein, an “agonist” is a substance that stimulates its bindingpartner, typically a receptor. Stimulation is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Stimulation may be defined with respect to anincrease in a particular effect or function that is induced byinteraction of the agonist or partial agonist with a binding partner andcan include allosteric effects.

As used herein, an “antagonist” is a substance that inhibits its bindingpartner, typically a receptor. Inhibition is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Inhibition may be defined with respect to adecrease in a particular effect or function that is induced byinteraction of the antagonist with a binding partner, and can includeallosteric effects.

As used herein, a “partial agonist” or a “partial antagonist” is asubstance that provides a level of stimulation or inhibition,respectively, to its binding partner that is not fully or completelyagonistic or antagonistic, respectively. It will be recognized thatstimulation, and hence, inhibition is defined intrinsically for anysubstance or category of substances to be defined as agonists,antagonists, or partial agonists.

As used herein, “intrinsic activity” or “efficacy” relates to somemeasure of biological effectiveness of the binding partner complex. Withregard to receptor pharmacology, the context in which intrinsic activityor efficacy should be defined will depend on the context of the bindingpartner (e.g., receptor/ligand) complex and the consideration of anactivity relevant to a particular biological outcome. For example, insome circumstances, intrinsic activity may vary depending on theparticular second messenger system involved. Where such contextuallyspecific evaluations are relevant, and how they might be relevant in thecontext of the present invention, will be apparent to one of ordinaryskill in the art.

As used herein, modulation of a receptor includes agonism, partialagonism, antagonism, partial antagonism, or inverse agonism of areceptor.

As will be appreciated by those skilled in the art, when treating aviral infection such as HCV, HBV, or HIV, such treatment may becharacterized in a variety of ways and measured by a variety ofendpoints. The scope of the present invention is intended to encompassall such characterizations.

In one embodiment, the method can be used to induce an immune responseagainst multiple epitopes of a viral infection in a human. Induction ofan immune response against viral infection can be assessed using anytechnique that is known by those of skill in the art for determiningwhether an immune response has occurred. Suitable methods of detectingan immune response for the present invention include, among others,detecting a decrease in viral load or antigen in a subject's serum,detection of IFN-gamma-secreting peptide specific T cells, and detectionof elevated levels of one or more liver enzymes, such as alaninetransferase (ALT) and aspartate transferase (AST). In one embodiment,the detection of IFN-gamma-secreting peptide specific T cells isaccomplished using an ELISPOT assay. Another embodiment includesreducing the viral load associated with HBV infection, including areduction as measured by PCR testing.

In some embodiments, the present invention provides a method of treatinga viral infection, comprising administering to a human in need thereof,a therapeutically effective amount of a crystalline form of Compound Ior pharmaceutical composition of the present invention. In someembodiments, the present invention provides a crystalline form ofCompound I for use in the treatment of a viral infection, comprisingadministering a therapeutically effective amount of a crystalline formof Compound I or a pharmaceutical composition of the present invention.In some embodiments, the present invention provides use of a crystallineform of Compound I for the treatment of a viral infection. In someembodiments, the present invention provides use of a crystalline form ofCompound I for the manufacture of a medicament for the treatment of aviral infection.

In another aspect, the present invention provides methods for treating ahepatitis B viral infection or a hepatitis C viral infection, whereineach of the methods includes the step of administering to a humansubject infected with hepatitis B virus or hepatitis C virus atherapeutically effective amount of a crystalline form of Compound I.Typically, the human subject is suffering from a chronic hepatitis Binfection or a chronic hepatitis C infection, although it is within thescope of the present invention to treat people who are acutely infectedwith HBV or HCV.

In some embodiments, the present invention provides a crystalline formof Compound I for use in the treatment of a hepatitis B viral infectionor a hepatitis C viral infection. In some embodiments, the presentinvention provides use of a crystalline form of Compound I for themanufacture of a medicament for the treatment of a hepatitis B viralinfection or a hepatitis C viral infection.

In some embodiments, the present invention provides a crystalline formof Compound I for use in the treatment of a hepatitis B viral infection.In some embodiments, the present invention provides use of a crystallineform of Compound I for the manufacture of a medicament for the treatmentof a hepatitis B viral infection.

Treatment in accordance with the present invention typically results inthe stimulation of an immune response against HBV or HCV in a humanbeing infected with HBV or HCV, respectively, and a consequent reductionin the viral load of HBV or HCV in the infected person. Examples ofimmune responses include production of antibodies (e.g., IgG antibodies)and/or production of cytokines, such as interferons, that modulate theactivity of the immune system. The immune system response can be a newlyinduced response, or can be boosting of an existing immune response. Inparticular, the immune system response can be seroconversion against oneor more HBV or HCV antigens.

The viral load can be determined by measuring the amount of HBV DNA orHCV DNA present in the blood. For example, blood serum HBV DNA can bequantified using the Roche COBAS Amplicor Monitor PCR assay (version2.0; lower limit of quantification, 300 copies/mL [57 IU/mL]) and theQuantiplex bDNA assay (lower limit of quantification, 0.7 MEq/mL; BayerDiagnostics, formerly Chiron Diagnostics, Emeryville, Calif.). Theamount of antibodies against specific HBV or HCV antigens (e.g.,hepatitis B surface antigen (HBsAG)) can be measured using suchart-recognized techniques as enzyme-linked immunoassays andenzyme-linked immunoabsorbent assays. For example, the amount ofantibodies against specific HBV or HCV antigens can be measured usingthe Abbott AxSYM microparticle enzyme immunoassay system (AbbottLaboratories, North Chicago, Ill.).

Compound I can be administered by any useful route and means, such as byoral or parenteral (e.g., intravenous) administration. Therapeuticallyeffective amounts of Compound I are from about 0.00001 mg/kg body weightper day to about 10 mg/kg body weight per day, such as from about 0.0001mg/kg body weight per day to about 10 mg/kg body weight per day, or suchas from about 0.001 mg/kg body weight per day to about 1 mg/kg bodyweight per day, or such as from about 0.01 mg/kg body weight per day toabout 1 mg/kg body weight per day, or such as from about 0.05 mg/kg bodyweight per day to about 0.5 mg/kg body weight per day, or such as fromabout 0.3 μg to about 30 mg per day, or such as from about 30 μg toabout 300 μg per day.

Therapeutically effective amounts of Compound I are also from about 0.01mg per dose to about 1000 mg per dose, such as from about 0.01 mg perdose to about 100 mg per dose, or such as from about 0.1 mg per dose toabout 100 mg per dose, or such as from about 1 mg per dose to about 100mg per dose, or such as from about 1 mg per dose to about 10 mg perdose. Other therapeutically effective amounts of Compound I are about 1mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg perdose. Other therapeutically effective amounts of Compound I are about100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350,400, 450, or about 500 mg per dose. A single dose can be administeredhourly, daily, or weekly. For example, a single dose can be administeredonce every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. Asingle dose can also be administered once every 1 day, 2, 3, 4, 5, 6, oronce every 7 days. A single dose can also be administered once every 1week, 2, 3, or once every 4 weeks. A single dose can also beadministered once every month.

The frequency of dosage of Compound I will be determined by the needs ofthe individual patient and can be, for example, once per day or twice,or more times, per day. Administration of Compound I continues for aslong as necessary to treat the HBV or HCV infection. For example,Compound I can be administered to a human being infected with HBV or HCVfor a period of from 20 days to 180 days or, for example, for a periodof from 20 days to 90 days or, for example, for a period of from 30 daysto 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of Compound I,followed by a period of several or more days during which a patient doesnot receive a daily dose of Compound I. For example, a patient canreceive a dose of Compound I every other day, or three times per week.Again by way of example, a patient can receive a dose of Compound I eachday for a period of from 1 to 14 days, followed by a period of 7 to 21days during which the patient does not receive a dose of Compound I,followed by a subsequent period (e.g., from 1 to 14 days) during whichthe patient again receives a daily dose of Compound I. Alternatingperiods of administration of Compound I, followed by non-administrationof Compound I, can be repeated as clinically required to treat thepatient.

As described more fully herein, crystalline forms of Compound I can beadministered with one or more additional therapeutic agent(s) to a humanbeing infected with hepatitis B virus or hepatitis C virus. Theadditional therapeutic agent(s) can be administered to the infectedhuman being at the same time as the crystalline form of Compound I, orbefore or after administration of the crystalline form of Compound I. Insome embodiments, the present invention provides a crystalline form ofCompound I, for use in a method of treating or preventing a hepatitis Bviral infection, wherein the crystalline form of Compound I isadministered simultaneously, separately or sequentially with one or moreadditional therapeutic agents for treating a hepatitis B viralinfection. In some embodiments, the present invention provides use of acrystalline form of Compound I for the manufacture of a medicament forthe treatment of a hepatitis B viral infection, wherein the crystallineform of Compound I is administered simultaneously, separately orsequentially with one or more additional therapeutic agents for treatinga hepatitis B viral infection.

In another aspect, the present invention provides a method forameliorating a symptom associated with an HBV infection or HCVinfection, wherein the method comprises administering to a human subjectinfected with hepatitis B virus or hepatitis C virus a therapeuticallyeffective amount of the crystalline form of Compound I, wherein thetherapeutically effective amount is sufficient to ameliorate a symptomassociated with the HBV infection or HCV infection. Such symptomsinclude the presence of HBV virus particles (or HCV virus particles) inthe blood, liver inflammation, jaundice, muscle aches, weakness andtiredness.

In some embodiments, the present invention provides a crystalline formof Compound I for use in ameliorating a symptom associated with an HBVinfection or HCV infection, wherein the method comprises administeringto a human subject infected with hepatitis B virus or hepatitis C virusa therapeutically effective amount of the crystalline form of CompoundI, wherein the therapeutically effective amount is sufficient toameliorate a symptom associated with the HBV infection or HCV infection.In some embodiments, the present invention provides use of a crystallineform of Compound I for the manufacture of a medicament for theameliorating a symptom associated with an HBV infection or HCVinfection, wherein the method comprises administering to a human subjectinfected with hepatitis B virus or hepatitis C virus a therapeuticallyeffective amount of the crystalline form of Compound I, wherein thetherapeutically effective amount is sufficient to ameliorate a symptomassociated with the HBV infection or HCV infection

In a further aspect, the present invention provides a method forreducing the rate of progression of a hepatitis B viral infection, or ahepatitis C virus infection, in a human being, wherein the methodcomprises administering to a human subject infected with hepatitis Bvirus or hepatitis C virus a therapeutically effective amount ofCompound I, or a pharmaceutically acceptable salt thereof, wherein thetherapeutically effective amount is sufficient to reduce the rate ofprogression of the hepatitis B viral infection or hepatitis C viralinfection. The rate of progression of the infection can be followed bymeasuring the amount of HBV virus particles or HCV virus particles inthe blood.

In another aspect, the present invention provides a method for reducingthe viral load associated with HBV infection or HCV infection, whereinthe method comprises administering to a human being infected with HBV orHCV a therapeutically effective amount of Compound I, or apharmaceutically acceptable salt thereof, wherein the therapeuticallyeffective amount is sufficient to reduce the HBV viral load or the HCVviral load in the human being.

In a further aspect, the present invention provides a method of inducingor boosting an immune response against Hepatitis B virus or Hepatitis Cvirus in a human being, wherein the method comprises administering atherapeutically effective amount of Compound I, or a pharmaceuticallyacceptable salt thereof, to the human being, wherein a new immuneresponse against Hepatitis B virus or Hepatitis C virus is induced inthe human being, or a preexisting immune response against Hepatitis Bvirus or Hepatitis C virus is boosted in the human being. Seroconversionwith respect to HBV or HCV can be induced in the human being. Examplesof immune responses include production of antibodies, such as IgGantibody molecules, and/or production of cytokine molecules thatmodulate the activity of one or more components of the human immunesystem.

Induction of seroconversion against HCV or HBV in patients chronicallyinfected with either of these viruses is an unexpected property ofCompound I. In clinical practice, an HBV patient, or HCV patient, istreated with Compound I, alone or in combination with one or more othertherapeutic agents, until an immune response against HBV or HCV isinduced or enhanced and the viral load of HBV or HCV is reduced.Thereafter, although the HBV or HCV virus may persist in a latent formin the patient's body, treatment with Compound I can be stopped, and thepatient's own immune system is capable of suppressing further viralreplication. In patients treated in accordance with the presentinvention and who are already receiving treatment with an antiviralagent that suppresses replication of the HBV virus or HCV virus, theremay be little or no detectable viral particles in the body of thepatient during treatment with the antiviral agent(s). In these patients,seroconversion will be evident when the antiviral agent(s) is no longeradministered to the patient and there is no increase in the viral loadof HBV or HCV.

In the practice of the present invention, an immune response is inducedagainst one or more antigens of HBV or HCV. For example, an immuneresponse can be induced against the HBV surface antigen (HBsAg), oragainst the small form of the HBV surface antigen (small S antigen), oragainst the medium form of the HBV surface antigen (medium S antigen),or against a combination thereof. Again by way of example, an immuneresponse can be induced against the HBV surface antigen (HBsAg) and alsoagainst other HBV-derived antigens, such as the core polymerase orx-protein.

Induction of an immune response against HCV or HBV can be assessed usingany technique that is known by those of skill in the art for determiningwhether an immune response has occurred. Suitable methods of detectingan immune response for the present invention include, among others,detecting a decrease in viral load in a subject's serum, such as bymeasuring the amount of HBV DNA or HCV DNA in a subject's blood using aPCR assay, and/or by measuring the amount of anti-HBV antibodies, oranti-HCV antibodies, in the subject's blood using a method such as anELISA.

Additionally, the compounds of this invention may be useful in thetreatment of cancer or tumors (including dysplasias, such as uterinedysplasia). These includes hematological malignancies, oral carcinomas(for example of the lip, tongue or pharynx), digestive organs (forexample esophagus, stomach, small intestine, colon, large intestine, orrectum), liver and biliary passages, pancreas, respiratory system suchas larynx or lung (small cell and non-small cell), bone, connectivetissue, skin (e.g., melanoma), breast, reproductive organs (uterus,cervix, testicles, ovary, or prostate), urinary tract (e.g., bladder orkidney), brain and endocrine glands such as the thyroid. In summary, thecompounds of this invention are employed to treat any neoplasm,including not only hematologic malignancies but also solid tumors of allkinds.

Hematological malignancies are broadly defined as proliferativedisorders of blood cells and/or their progenitors, in which these cellsproliferate in an uncontrolled manner. Anatomically, the hematologicmalignancies are divided into two primary groups: lymphomas—malignantmasses of lymphoid cells, primarily but not exclusively in lymph nodes,and leukemias—neoplasm derived typically from lymphoid or myeloid cellsand primarily affecting the bone marrow and peripheral blood. Thelymphomas can be subdivided into Hodgkin's Disease and Non-Hodgkin'slymphoma (NHL). The latter group comprises several distinct entities,which can be distinguished clinically (e.g. aggressive lymphoma,indolent lymphoma), histologically (e.g. follicular lymphoma, mantlecell lymphoma) or based on the origin of the malignant cell (e.g. Blymphocyte, T lymphocyte). Leukemias and related malignancies includeacute myelogenous leukemia (AML), chronic myelogenous leukemia (CML),acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia(CLL). Other hematological malignancies include the plasma celldyscrasias including multiple myeloma, and the myelodysplasticsyndromes.

VII. Combination Therapy

Subjects being treated by administration of the solid forms of CompoundI described herein can benefit from treatment with additionaltherapeutic agents that are effective in treating HCV, or enhance theanti-HCV therapeutic effect of Compound I forms, in accordance with someembodiments. Additional therapeutic agents that may be useful for thispurpose include, but are not limited to, ribavirin,

Other antiviral agents that may be useful in combination with thecrystalline forms of Compound I of the present invention, include, butare not limited to: HCV NS3 protease inhibitors (see EP 1881001, US2003187018, US 2005267018, WO 2003006490, WO 200364456, WO 2004094452,WO 2005028502, WO 2005037214, WO 2005095403, WO 2007014920, WO2007014921, WO 2007014922, WO 2007014925, WO 2007014926, WO 2007015824,WO 2008010921, and WO 2008010921); HCV NS5B Inhibitors (see US2004229840, US 2005154056, US 2005-98125, US 20060194749, US20060241064, US 20060293306, US 2006040890, US 2006040927, US2006166964, US 2007275947, U.S. Pat. No. 6,784,166, US20072759300, WO2002057287, WO 2002057425, WO 2003010141, WO 2003037895, WO 2003105770,WO 2004000858, WO 2004002940, WO 2004002944, WO 2004002977, WO2004003138, WO 2004041201, WO 2004065367, WO 2004096210, WO 2005021568,WO 2005103045, WO 2005123087, WO 2006012078, WO 2006020082, WO2006065335, WO 2006065590, WO 2006093801, WO 200702602, WO 2007039142,WO 2007039145, WO 2007076034, WO 2007088148, WO 2007092000, andWO2007095269); HCV NS4 Inhibitors (see WO 2005067900 and WO 2007070556);HCV NS5a Inhibitors (see US 2006276511, WO 2006035061, WO 2006100310, WO2006120251, and WO 2006120252); Toll-like receptor agonists (see WO2007093901); other inhibitors (see WO 2000006529, WO 2003101993, WO2004009020, WO 2004014313, WO 2004014852, and WO 2004035571); U.S. Pat.No. 7,429,572; US 2007/0197463; US 2010/0081628; US 2010/0016251; U.S.Ser. No. 12/783,680; telaprevir (also known as VX-950, which isdisclosed in US 2010/0015090); boceprevir (disclosed in US2006/0276405); BMS-790052 (disclosed in WO 2008/021927); ITMN-191(disclosed in US 2009/0269305 at Example 62-1); ANA-598 (identified ascompound 31 in F. Ruebasam et al. Biorg. Med. Chem. Lett. (2008) 18:3616-3621; and TMC435 (formerly known as TMC435350); as well as,interferon-α, interferon-β, pegylated interferon-α, ribavirin,levovirin, viramidine, another nucleoside HCV polymerase inhibitor, aHCV non-nucleoside polymerase inhibitor, a HCV protease inhibitor, a HCVhelicase inhibitor or a HCV fusion inhibitor.

The present disclosure is not to be limited in scope by the specificembodiments disclosed in the examples, which are intended to beillustrations of a few embodiments of the disclosure, nor is thedisclosure to be limited by any embodiments that are functionallyequivalent within the scope of this disclosure. Indeed, variousmodifications of the disclosure in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims. To this end, it shouldbe noted that one or more hydrogen atoms or methyl groups can be omittedfrom the drawn structures consistent with accepted shorthand notation ofsuch organic compounds, and that one skilled in the art of organicchemistry would readily appreciate their presence.

In certain embodiments, a method for treating or preventing an HBVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein (e.g. any crystallineform of Compound I), in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, four, one or two, or oneto three, or one to four) additional therapeutic agents. In oneembodiment, a method for treating an HBV infection in a human having orat risk of having the infection is provided, comprising administering tothe human a therapeutically effective amount of a compound disclosedherein (e.g. any crystalline form of Compound I), in combination with atherapeutically effective amount of one or more (e.g., one, two, three,four, one or two, or one to three, or one to four) additionaltherapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating an HBV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein (e.g. any crystalline form of Compound I), in combination with atherapeutically effective amount of one or more additional therapeuticagents which are suitable for treating an HBV infection.

In certain embodiments, a compound as disclosed herein (e.g., anycrystalline form of Compound I) may be combined with one or moreadditional therapeutic agents in any dosage amount of the crystallineform of Compound I (e.g., from 1 mg to 1000 mg of compound).

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein (e.g. any crystalline form of Compound I), incombination with one or more (e.g., one, two, three, four, one or two,or one to three, or one to four) additional therapeutic agents, and apharmaceutically acceptable carrier, diluent or excipient are provided.

In one embodiment, kits comprising a compound disclosed herein (e.g. anycrystalline form of Compound I), in combination with one or more (e.g.,one, two, three, four, one or two, or one to three, or one to four)additional therapeutic agents are provided.

In the above embodiments, the additional therapeutic agent may be ananti-HBV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of HBVcombination drugs, HBV DNA polymerase inhibitors, immunomodulators,toll-like receptor modulators (modulators of TLR1, TLR2, TLR3, TLR4,TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13), interferonalpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7,hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surfaceantigen (HBsAg) secretion or assembly inhibitors, compounds targetinghepatitis B core antigen (HBcAg), cyclophilin inhibitors, HBVtherapeutic vaccines, HBV prophylactic vaccines, HBV viral entryinhibitors, NTCP (Na+-taurocholate cotransporting polypeptide)inhibitors, antisense oligonucleotide targeting viral mRNA, shortinterfering RNAs (siRNA), miRNA gene therapy agents, endonucleasemodulators, inhibitors of ribonucleotide reductase, hepatitis B virus Eantigen inhibitors, recombinant scavenger receptor A (SRA) proteins, Srckinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetichairpin RNAs (sshRNAs), HBV antibodies including HBV antibodiestargeting the surface antigens of the hepatitis B virus and bispecificantibodies and “antibody-like” therapeutic proteins (such as DARTs®),Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives, TCR-likeantibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines,nucleoprotein modulators (HBV core or capsid protein modulators),stimulators of retinoic acid-inducible gene 1, stimulators of NOD2,stimulators of NOD1, Arginase-1 inhibitors, STING agonists, PI3Kinhibitors, lymphotoxin beta receptor activators, Natural Killer CellReceptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA4)inhibitors, IDO inhibitors, cccDNA epigenetic modifiers, CD137inhibitors, Killer cell lectin-like receptor subfamily G member 1inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors,CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-InterferonLambda, recombinant thymosin alpha-1, BTK inhibitors, modulators ofTIGIT, modulators of CD47, modulators of SIRPalpha, modulators of ICOS,modulators of CD27, modulators of CD70, modulators of OX40, modulatorsof NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3,modulators of NKG2A, modulators of GITR, modulators of CD160, modulatorsof HEVEM, modulators of CD161, modulators of Ax1, modulators of Mer,modulators of Tyro, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs),IAPs inhibitors, SMAC mimetics, Hepatitis B virus replication inhibitorscompounds such as those disclosed in US20100143301 (Gilead Sciences),US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), U.S.Pat. No. 8,722,054 (Gilead Sciences), US20140045849 (Janssen),US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221(Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen),WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050(Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485(Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (VentirxPharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics),US20130251673 (Novira therapeutics), U.S. Pat. No. 8,513,184 (GileadSciences), US20140030221 (Gilead Sciences), US20130344030 (GileadSciences), US20130344029 (Gilead Sciences), US20140343032 (Roche),WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen),WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen),US20140330015 (Ono pharmaceutical), US20130079327 (Ono pharmaceutical),US20130217880 (Ono pharmaceutical), US20100015178 (Incyte) and otherdrugs for treating HBV, and combinations thereof.

In certain embodiments, the additional therapeutic is selected from thegroup consisting of HBV combination drugs, HBV DNA polymeraseinhibitors, toll-like receptor 7 modulators, toll-like receptor 8modulators, Toll-like receptor 7 and 8 modulators, Toll-like receptor 3modulators, interferon alpha receptor ligands, HBsAg inhibitors,hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors,compounds targeting HBcAg, cyclophilin inhibitors, HBV therapeuticvaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCPinhibitors, antisense oligonucleotide targeting viral mRNA, shortinterfering RNAs (siRNA), hepatitis B virus E antigen inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodiestargeting the surface antigens of the hepatitis B virus, thymosinagonists, cytokines, nucleoprotein modulators (HBV core or capsidprotein modulators), stimulators of retinoic acid-inducible gene 1,stimulators of NOD2, stimulators of NOD1, recombinant thymosin alpha-1,BTK inhibitors, IDO inhibitors, hepatitis B virus replicationinhibitors, and combinations thereof.

In certain embodiments a crystalline form of Compound I is formulated asa tablet, which may optionally contain one or more other compoundsuseful for treating HBV. In certain embodiments, the tablet can containanother active ingredient for treating HBV, such as HBV DNA polymeraseinhibitors, immunomodulators, toll-like receptor modulators (modulatorsof TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11,TLR12 and TLR13), modulators of TLR7, modulators of TLR8, modulators ofTLR7 and TLR8, interferon alpha receptor ligands, hyaluronidaseinhibitors, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis Bsurface antigen (HBsAg) secretion or assembly inhibitors, compoundstargeting hepatitis B core antigen (HBcAg), cyclophilin inhibitors, HBVviral entry inhibitors, NTCP (Na+-taurocholate cotransportingpolypeptide) inhibitors, endonuclease modulators, inhibitors ofribonucleotide reductase, hepatitis B virus E antigen inhibitors, Srckinase inhibitors, HBx inhibitors, cccDNA inhibitors, CCR2 chemokineantagonists, thymosin agonists, nucleoprotein modulators (HBV core orcapsid protein modulators), stimulators of retinoic acid-inducible gene1, stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors,STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators,Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene3 inhibitors, CDI60 inhibitors, cytotoxic T-lymphocyte-associatedprotein 4 (CTLA4) inhibitors, CD137 inhibitors, Killer cell lectin-likereceptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- andT-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors,PD-L1 inhibitors, BTK inhibitors, modulators of TIGIT, cccDNA epigeneticmodifiers, modulators of CD47, modulators of SIRP alpha, modulators ofICOS, modulators of CD27, modulators of CD70, modulators of OX40,modulators of NKG2D, modulators of Tim-4, modulators of B7-H4,modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulatorsof CD160, modulators of HEVEM, modulators of CD161, modulators of Ax1,modulators of Mer, modulators of Tyro, IAPs inhibitors, SMAC mimetics,IDO inhibitors, and Hepatitis B virus replication inhibitors, andcombinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Combination drugs selected from the group consisting of    tenofovir disoproxil fumarate+emtricitabine (TRUVADA®),    ABX-203+lamivudine+PEG-IFNalpha, and ABX-203+adefovir+PEG-IFNalpha,    INO-9112+RG7944 (INO-1800);-   (2) HBV DNA polymerase inhibitors selected from the group consisting    of besifovir, entecavir (Baraclude®), adefovir (Hepsera®), tenofovir    disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir,    tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir    alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil    fumarate, tenofovir octadecyloxyethyl ester, telbivudine (Tyzeka®),    pradefovir, Clevudine, emtricitabine (Emtriva®), ribavirin,    lamivudine (Epivir-HBV®), phosphazide, famciclovir, SNC-019754,    FMCA, fusolin, AGX-1009, AR-II-04-26, HS-10234 and metacavir;-   (3) Immunomodulators selected from the group consisting of    rintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil    (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil    (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10,    ribavirin, IL-12, INO-9112, polymer polyethyleneimine (PEI), Gepon,    VGV-1, MOR-22, BMS-936559, RO-7011785, RO-6871765 and IR-103;-   (4) Toll-like receptor 7 modulators selected from the group    consisting of GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434,    DSP-3025, IMO-4200, MCT-465, 3M-051, SB-9922, 3M-052, Limtop,    TMX-30X, TMX-202 RG-7863 and RG-7795;-   (5) Toll-like receptor 8 modulators selected from the group    consisting of motolimod, resiquimod, 3M-051, 3M-052, MCT-465,    IMO-4200, VTX-763, VTX-1463;-   (6) Toll-like receptor 3 modulators selected from the group    consisting of rintatolimod, poly-ICLC, MCT-465, MCT-475, Riboxxon,    Riboxxim and ND-1.1;-   (7) Interferon alpha receptor ligands selected from the group    consisting of interferon alpha-2b (Intron A®), pegylated interferon    alpha-2a (Pegasys®), interferon alpha 1b (Hapgen®), Veldona,    Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a),    P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co    (recombinant super compound interferon), Ypeginterferon alfa-2b    (YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-Intron®),    Bioferon, Novaferon, Inmutag (Inferon), Multiferon®, interferon    alfa-n1 (Humnoferon®), interferon beta-1a (Avonex®), Shaferon,    interferon alfa-2b (AXXO), Alfaferone, interferon alfa-2b    (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG,    BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion,    Pegaferon, PDferon-B PDferon-B, interferon alfa-2b (IFN,    Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano,    Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila). Optipeg A,    Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b    (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon,    Uniferon, Urifron, interferon alfa-2b (Changchun Institute of    Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng    Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b and    Interapo (Interapa);-   (8) Hyaluronidase inhibitors selected from the group consisting of    astodrimer;-   (9) Modulators of IL-10;-   (10) HBsAg inhibitors selected from the group consisting of    HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9,    REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165,    REP-2053, REP-2031 and REP-006 and REP-9AC′;-   (11) Toll like receptor 9 modulators selected from CYT003 and    CYT-003-QbG10;-   (12) Cyclophilin inhibitors selected from the group consisting of    OCB-030, SCY-635 and NVP-018;-   (13) HBV Prophylactic vaccines selected from the group consisting of    Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B,    D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine,    Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay,    hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07,    GSK-223192A, Engerix B®, recombinant hepatitis B vaccine    (intramuscular, Kangtai Biological Products), recombinant hepatitis    B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan    Biological Engineering), Bimmugen, Euforavac, Eutravac,    anrix-DTaP-IPV-Hep B, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin    DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep    B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac    HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,    SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,    Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine,    and DTaP-rHB-Hib vaccine;-   (14) HBV Therapeutic vaccines selected from the group consisting of    HBsAG-HBIG complex, Bio-Hep-B, NASVAC, abi-HB (intravenous),    ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine    (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC,    Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB,    VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im/TriGrid/antigen    vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800),    recombinant VLP-based therapeutic vaccine (HBV infection, VLP    Biotech), AdTG-17909, AdTG-17910 AdTG-18202, ChronVac-B, and Lm HBV;-   (15) HBV viral entry inhibitor selected from the group consisting of    Myrcludex B;-   (16) Antisense oligonucleotide targeting viral mRNA selected from    the group consisting of ISIS-HBVRx;-   (17) short interfering RNAs (siRNA) selected from the group    consisting of TKM-HBV (TKM-HepB), ALN-HBV, SR-008, ddRNAi and    ARC-520;-   (18) Endonuclease modulators selected from the group consisting of    PGN-514;-   (19) Inhibitors of ribonucleotide reductase selected from the group    consisting of Trimidox;-   (20) Hepatitis B virus E antigen inhibitors selected from the group    consisting of wogonin;-   (21) HBV antibodies targeting the surface antigens of the hepatitis    B virus selected from the group consisting of GC-1.102, XTL-17,    XTL-19, XTL-001, KN-003, IV Hepabulin SN, and fully human monoclonal    antibody therapy (hepatitis B virus infection, Humabs BioMed);-   (22) HBV antibodies including monoclonal antibodies and polyclonal    antibodies selected from the group consisting of Zutectra, Shang    Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B,    Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24,    hepatitis B immunoglobulin (intravenous, pH4, HBV infection,    Shanghai RAAS Blood Products) and Fovepta (BT-088);-   (23) CCR2 chemokine antagonists selected from the group consisting    of propagermanium,-   (24) Thymosin agonists selected from the group consisting of    Thymalfasin;-   (25) Cytokines selected from the group consisting of recombinant    IL-7, CYT-107, interleukin-2 (IL-2, Immunex); recombinant human    interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24 and    celmoleukin;-   (26) Nucleoprotein modulators (HBV core or capsid protein    modulators) selected from the group consisting of NVR-1221,    NVR-3778, BAY 41-4109, morphothiadine mesilate and DVR-23;-   (27) Stimulators of retinoic acid-inducible gene 1 selected from the    group consisting of SB-9200, SB-40, SB-44, ORI-7246, ORI-9350,    ORI-7537, ORI-9020, ORI-9198 and ORI-7170;-   (28) Stimulators of NOD2 selected from the group consisting of    SB-9200;-   (29) Recombinant thymosin alpha-1 selected from the group consisting    of NL-004 and PEGylated thymosin alpha 1:-   (30) Hepatitis B virus replication inhibitors selected from the    group consisting of isothiafludine, IQP-HBV, RM-5038 and Xingantie;-   (31) PI3K inhibitors selected from the group consisting of    idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib,    rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib,    duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584,    copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,    panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093,    pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,    RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib,    LY-3023414, SAR-260301 and CLR-1401;-   (32) cccDNA inhibitors selected from the group consisting of    BSBI-25;-   (33) PD-L1 inhibitors selected from the group consisting of    MEDI-0680, RG-7446, durvalumab, KY-1003, KD-033, MSB-0010718C,    TSR-042, ALN-PDL, STI-A1014 and BMS-936559;-   (34) PD-1 inhibitors selected from the group consisting of    nivolumab, pembrolizumab, pidilizumab, BGB-108 and mDX-400;-   (35) BTK inhibitors selected from the group consisting of ACP-196,    dasatinib, ibrutinib, PRN-1008, SNS-062, ONO-4059, BGB-3111,    MSC-2364447, X-022, spebrutinib, TP-4207, HM-71224, KBP-7536 and    AC-0025;-   (36) IDO inhibitors selected from the group consisting of    epacadostat (INCB24360), F-001287, resminostat (4SC-201), SN-35837,    NLG-919, GDC-0919, and indoximod;-   (37) Other drugs for treating HBV selected from the group consisting    of gentiopicrin (gentiopicroside), nitazoxanide, birinapant, NOV-205    (Molixan; BAM-205), Oligotide, Mivotilate, Feron, levamisole, Ka Shu    Ning, Alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm,    KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5),    HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA,    Hepuyinfen, DasKloster 0014-01, Jiangantai (Ganxikang), picroside,    DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced    glutathione, RO-6864018 and ZH-2N; and-   (37) The compounds disclosed in US20100143301 (Gilead Sciences),    US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences),    U.S. Pat. No. 8,722,054 (Gilead Sciences), US20140045849 (Janssen),    US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221    (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen),    WO02014/023813 (Janssen), US20080234251 (Array Biopharma),    US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma),    US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma),    US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma),    US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma),    US20140275167 (Novira therapeutics), US20130251673 (Novira    therapeutics), U.S. Pat. No. 8,513,184 (Gilead Sciences),    US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences),    US20130344029 (Gilead Sciences), US20140343032 (Roche), WO2014037480    (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176    (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen),    US20140330015 (Ono pharmaceutical), US20130079327 (Ono    pharmaceutical), and US20130217880 (Ono pharmaceutical), and    US20100015178 (Incyte).

In certain embodiments, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with one, two, three, fouror more additional therapeutic agents. In certain embodiments, acompound disclosed herein (e.g. any crystalline form of Compound I), iscombined with two additional therapeutic agents. In other embodiments, acompound disclosed herein (e.g. any crystalline form of Compound I), iscombined with three additional therapeutic agents. In furtherembodiments, a compound disclosed herein (e.g. any crystalline form ofCompound I), is combined with four additional therapeutic agents. Theone, two, three, four or more additional therapeutic agents can bedifferent therapeutic agents selected from the same class of therapeuticagents, and/or they can be selected from different classes oftherapeutic agents.

In a specific embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with an HBV DNA polymeraseinhibitor. In another specific embodiment, a compound disclosed herein(e.g. any crystalline form of Compound I), is combined with an HBV DNApolymerase inhibitor and at least one additional therapeutic agentselected from the group consisting of: immunomodulators, toll-likereceptor modulators (modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13), interferon alphareceptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAginhibitors, hepatitis B surface antigen (HBsAg) secretion or assemblyinhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBVtherapeutic vaccines, HBV prophylactic vaccines HBV viral entryinhibitors, NTCP inhibitors, antisense oligonucleotide targeting viralmRNA, short interfering RNAs (siRNA), miRNA gene therapy agents,endonuclease modulators, inhibitors of ribonucleotide reductase,Hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A(SRA) proteins, src kinase inhibitors, HBx inhibitors, cccDNAinhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodiesincluding HBV antibodies targeting the surface antigens of the hepatitisB virus and bispecific antibodies and “antibody-like” therapeuticproteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fabderivatives, TCR-like antibodies), CCR2 chemokine antagonists, thymosinagonists, cytokines, nucleoprotein modulators (HBV core or capsidprotein modulators), stimulators of retinoic acid-inducible gene 1,stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors. STINGagonists, PI3K inhibitors, lymphotoxin beta receptor activators, NaturalKiller Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein4 (CTLA4) inhibitors, CD137 inhibitors, Killer cell lectin-like receptorsubfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyteattenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1, BTKinhibitors, modulators of TIGIT, modulators of CD47, modulators ofSIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70,modulators of OX40, cccDNA epigenetic modifiers, modulators of NKG2D,modulators of Tim-4, modulators of B7-H4, modulators of B7-H3,modulators of NKG2A, modulators of GITR, modulators of CD160, modulatorsof HEVEM, modulators of CD161, modulators of Ax1, modulators of Mer,modulators of Tyro, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs),IAPs inhibitors, SMAC mimetics, IDO inhibitors, and Hepatitis B virusreplication inhibitors.

In another specific embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with an HBV DNA polymeraseinhibitor and at least a second additional therapeutic agent selectedfrom the group consisting of: immunomodulators, toll-like receptormodulators (modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7,TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13), HBsAg inhibitors, HBVtherapeutic vaccines, HBV antibodies including HBV antibodies targetingthe surface antigens of the hepatitis B virus and bispecific antibodiesand antibody-like therapeutic proteins (such as DARTs®, Duobodies®,Bites®, XmAbs®, TandAbs®, Fab derivatives, TCR-like antibodies),cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1,PD-1 inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3Kinhibitors, IDO inhibitors, and stimulators of NOD2.

In another specific embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with an HBV DNA polymeraseinhibitor and at least a second additional therapeutic agent selectedfrom the group consisting of: HBV viral entry inhibitors, NTCPinhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targetingthe surface antigens of the hepatitis B virus, short interfering RNAs(siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs(sshRNAs), and nucleoprotein modulators (HBV core or capsid proteinmodulators).

In another specific embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with an HBV DNA polymeraseinhibitor, one or two additional therapeutic agents selected from thegroup consisting of: immunomodulators, toll-like receptor modulators(modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9,TLR10, TLR11, TLR12 and TLR13), HBsAg inhibitors, hepatitis B surfaceantigen (HBsAg) secretion or assembly inhibitors, HBV therapeuticvaccines, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies andantibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®,XmAbs®, TandAbs®, Fab derivatives, TCR-like antibodies), cyclophilininhibitors, stimulators of retinoic acid-inducible gene 1, PD-1inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3K inhibitors,IDO inhibitors, and stimulators of NOD2, and one or two additionaltherapeutic agents selected from the group consisting of: HBV viralentry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors,HBV antibodies targeting the surface antigens of the hepatitis B virus,short interfering RNAs (siRNA), miRNA gene therapy agents, shortsynthetic hairpin RNAs (sshRNAs), and nucleoprotein modulators (HBV coreor capsid protein modulators).

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with one, two, three, fouror more additional therapeutic agents selected from adefovir (Hepsera®),tenofovir disoproxil fumarate+emtricitabine (TRUADA®), tenofovirdisoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine(Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,telbivudine (Tyzeka®), Clevudine, emtricitabine (Emtriva®),peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b(Hapgen®), interferon alpha-2b (Intron A®), pegylated interferonalpha-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin,interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon),Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b(AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron,interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B,BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega),Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b(Changchun Institute of Biological Products), Anterferon, Shanferon,MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2(Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleukin.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®).

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) orlamivudine (Epivir-HBV®). In a particular embodiment, a compounddisclosed herein (e.g. any crystalline form of Compound I) is combinedwith a PD-1 inhibitor. In a particular embodiment, a compound disclosedherein (e.g. any crystalline form of Compound I) is combined with aPD-L1 inhibitor. In a particular embodiment, a compound disclosed herein(e.g. any crystalline form of Compound I) is combined with an IDOinhibitor. In a particular embodiment, a compound disclosed herein (e.g.any crystalline form of Compound I) is combined with an IDO inhibitorand a PD-1 inhibitor. In a particular embodiment, a compound disclosedherein (e.g. any crystalline form of Compound I) is combined with an IDOinhibitor and a PD-L1 inhibitors.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with a first additionaltherapeutic agent selected from the group consisting of: entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a secondadditional therapeutic agent selected from the group consisting ofimmunomodulators, toll-like receptor modulators (modulators of TLR1,TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 andTLR13), interferon alpha receptor ligands, hyaluronidase inhibitors,recombinant IL-7, HBsAg inhibitors, hepatitis B surface antigen (HBsAg)secretion or assembly inhibitors, compounds targeting HbcAg, cyclophilininhibitors, HBV Therapeutic vaccines, HBV prophylactic vaccines, HBVviral entry inhibitors, NTCP inhibitors, antisense oligonucleotidetargeting viral mRNA, short interfering RNAs (siRNA), miRNA gene therapyagents, endonuclease modulators, inhibitors of ribonucleotide reductase,Hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A(SRA) proteins, src kinase inhibitors, HBx inhibitors, cccDNAinhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodiesincluding HBV antibodies targeting the surface antigens of the hepatitisB virus and bispecific antibodies and antibody-like therapeutic proteins(such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives,TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists,cytokines, nucleoprotein modulators (HBV core or capsid proteinmodulators), stimulators of retinoic acid-inducible gene 1, stimulatorsof NOD2, stimulators of NOD1, IDO inhibitors, recombinant thymosinalpha-1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors,lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors,cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors, CD137inhibitors, Killer cell lectin-like receptor subfamily G member 1inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors,cccDNA epigenetic modifiers, CD305 inhibitors, PD-1 inhibitors, PD-L1inhibitors, PEG-Interferon Lambd, BTK inhibitors, modulators of TIGIT,modulators of CD47, modulators of SIRPalpha, modulators of ICOS,modulators of CD27, modulators of CD70, modulators of OX40, modulatorsof NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3,modulators of NKG2A, modulators of GITR, modulators of CD160, modulatorsof HEVEM, modulators of CDI61, modulators of Ax1, modulators of Mer,modulators of Tyro, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs),IAPs inhibitors, SMAC mimetics, and Hepatitis B virus replicationinhibitors.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with a first additionaltherapeutic agent selected from the group consisting of: entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a secondadditional therapeutic agent selected from the group consisting ofpeginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b(Hapgen®), interferon alpha-2b (Intron A®), pegylated interferonalpha-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin,interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon),Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b(AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron,interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B,BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega),Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b(Changchun Institute of Biological Products), Anterferon, Shanferon,MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2(Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleukin;

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with a first additionaltherapeutic agent selected from the group consisting of: entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a secondadditional therapeutic agent selected from the group consisting ofimmunomodulators, toll-like receptor modulators (modulators of TLR1,TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 andTLR13), HBsAg inhibitors, hepatitis B surface antigen (HBsAg) secretionor assembly inhibitors, HBV therapeutic vaccines, HBV antibodiesincluding HBV antibodies targeting the surface antigens of the hepatitisB virus and bispecific antibodies and antibody-like therapeutic proteins(such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives,TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, Arginase-1 inhibitors, PI3K inhibitors, PD-1inhibitors, PD-L inhibitors, IDO inhibitors, and stimulators of NOD2.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with a first additionaltherapeutic agent selected from the group consisting of: entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a secondadditional therapeutic agent selected from the group consisting of HBVviral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNAinhibitors, HBV antibodies targeting the surface antigens of thehepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapyagents, short synthetic hairpin RNAs (sshRNAs), and nucleoproteinmodulators (HBV core or capsid protein modulators).

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with a first additionaltherapeutic agent selected from the group consisting of: entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®), one or two additionaltherapeutic agents selected from the group consisting of:immunomodulators, toll-like receptor modulators (modulators of TLR1,TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 andTLR13), HBsAg inhibitors, hepatitis B surface antigen (HBsAg) secretionor assembly inhibitors, HBV therapeutic vaccines, HBV antibodiesincluding HBV antibodies targeting the surface antigens of the hepatitisB virus and bispecific antibodies and “antibody-like” therapeuticproteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fabderivatives, TCR-like antibodies), cyclophilin inhibitors, stimulatorsof retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors,Arginase-1 inhibitors, PI3K inhibitors, IDO inhibitors, and stimulatorsof NOD2, and one or two additional therapeutic agents selected from thegroup consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies targeting the surfaceantigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNAgene therapy agents, short synthetic hairpin RNAs (sshRNAs), andnucleoprotein modulators (HBV core or capsid protein modulators).

In certain embodiments, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with 5-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide. In certain embodiments, a compound disclosed herein (e.g.any crystalline form of Compound I), is combined with 5-10; 5-15; 5-20;5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certainembodiments, a compound disclosed herein (e.g. any crystalline form ofCompound I), is combined with 10 mg tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certainembodiments, a compound disclosed herein (e.g. any crystalline form ofCompound I), is combined with 25 mg tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide. A compoundas disclosed herein (e.g., a crystalline form of Compound I) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 1 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed.

In certain embodiments, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with 100-400 mg tenofovirdisoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovirdisoproxil. In certain embodiments, a compound disclosed herein (e.g.any crystalline form of Compound I), is combined with 100-150; 100-200,100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400;200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. In certain embodiments, a compound disclosedherein (e.g. any crystalline form of Compound I), is combined with 300mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. In certain embodiments, a compound disclosedherein (e.g. any crystalline form of Compound I), is combined with 250mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. In certain embodiments, a compound disclosedherein (e.g. any crystalline form of Compound I), is combined with 150mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. A compound as disclosed herein (e.g., acrystalline form of Compound I) may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 1 mg to 500 mgof compound) the same as if each combination of dosages werespecifically and individually listed.

In certain embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein (e.g. any crystallineform of Compound I), in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents. In one embodiment, a method fortreating an HIV infection in a human having or at risk of having theinfection is provided, comprising administering to the human atherapeutically effective amount of a compound disclosed herein (e.g.any crystalline form of Compound I), in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt, thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

A compound as disclosed herein (e.g. any crystalline form of Compound I)may be combined with one or more additional therapeutic agents in anydosage amount of the compound of Formula I (e.g., from 1 mg to 1000 mgof compound).

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein (e.g. any crystalline form of Compound I), incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent or excipient are provided.

In one embodiment, kits comprising a compound disclosed herein (e.g. anycrystalline form of Compound I), in combination with one or more (e.g.,one, two, three, one or two, or one to three) additional therapeuticagents are provided.

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachmentinhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidaseinhibitors, HIV vaccines, HIV maturation inhibitors, latency reversingagents (e.g., histone deacetylase inhibitors, proteasome inhibitors,protein kinase C (PKC) activators, and BRD4 inhibitors), compounds thattarget the HIV capsid (capsid inhibitors; e.g., capsid polymerizationinhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7)inhibitors, HIV p24 capsid protein inhibitors), pharmacokineticenhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-L1modulators, toll like receptors modulators, IL-15 agonists,), HIVantibodies, bispecific antibodies and antibody-like therapeutic proteins(e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives)including those targeting HIV gp120 or gp41, combination drugs for HIV,HIV p17 matrix protein inhibitors, IL-13 antagonists, Peptidyl-prolylcis-trans isomerase A modulators, Protein disulfide isomeraseinhibitors, Complement C5a receptor antagonists, DNA methyltransferaseinhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,Integrin antagonists, Nucleoprotein inhibitors, Splicing factormodulators, COMM domain containing protein 1 modulators, HIVRibonuclease H inhibitors, Retrocyclin modulators, CDK-9 inhibitors,Dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,Ubiquitin ligase inhibitors, Deoxycytidine kinase inhibitors, Cyclindependent kinase inhibitors Proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, HIV gene therapy, PI3K inhibitors, compounds such asthose disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489(University of Pennsylvania), WO 2013/091096A1 (Boehringer Ingelheim),WO 2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco),US20140221378 (Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim), WO2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences),WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences),WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO2012/003498 (Gilead Sciences) and WO 2013/006792 (Pharma Resources), andother drugs for treating HIV, and combinations thereof.

In certain embodiments, the additional therapeutic is selected from thegroup consisting of HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,pharmacokinetic enhancers, and combinations thereof.

In certain embodiments a crystalline form of Compound I is formulated asa tablet, which may optionally contain one or more other compoundsuseful for treating HIV. In certain embodiments, the tablet can containanother active ingredient for treating HIV, such as HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, pharmacokinetic enhancers, andcombinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Combination drugs selected from the group consisting of ATRIPLA®    (efavirenz+tenofovir disoproxil fumarate+emtricitabine), COMPLERA®    (EVIPLERA®, rilpivirine+tenofovir disoproxil    fumarate+emtricitabine), STRIBILD®    (elvitegravir+cobicistat+tenofovir disoproxil    fumarate+emtricitabine), dolutegravir+abacavir sulfate+lamivudine,    TRIUMEQ® (dolutegravir+abacavir+lamivudine),    lamivudine+nevirapine+zidovudine, dolutegravir+rilpivirine,    dolutegravir+rilpivirine hydrochloride, atazanavir    sulfate+cobicistat, atazanavir+cobicistat, darunavir+cobicistat,    efavirenz+lamivudine+tenofovir disoproxil fumarate, tenofovir    alafenamide hemifumarate+emtricitabine+cobicistat+elvitegravir,    tenofovir alafenamide hemifumarate+emtricitabine, tenofovir    alafenamide+emtricitabine, tenofovir alafenamide    hemifumarate+emtricitabine+rilpivirine, tenofovir    alafenamide+emtricitabine+rilpivirine, Vacc-4x+romidepsin,    darunavir+tenofovir alafenamide    hemifumarate+emtricitabine+cobicistat, APH-0812,    raltegravir+lamivudine, KALETRA® (ALUVIA®, lopinavir+ritonavir),    atazanavir sulfate+ritonavir, COMBIVIR® (zidovudine+lamivudine,    AZT+3TC), EPZICOM® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC),    TRIZIVIR® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC),    TRUVADA® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC),    doravirine+lamivudine+tenofovir disoproxil fumarate,    doravirine+lamivudine+tenofovir disoproxil, tenofovir+lamivudine and    lamivudine+tenofovir disoproxil fumarate;-   (2) HIV protease inhibitors selected from the group consisting of    amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium,    indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir,    nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir,    brecanavir, darunavir, DG-17, TMB-657 (PPL-100) and TMC-310911;-   (3) HIV non-nucleoside or non-nucleotide inhibitors of reverse    transcriptase selected from the group consisting of delavirdine,    delavirdine mesylate, nevirapine, etravirine, dapivirine,    doravirine, rilpivirine, efavirenz, KM-023, VM-1500, lentinan and    AIC-292;-   (4) HIV nucleoside or nucleotide inhibitors of reverse transcriptase    selected from the group consisting of VIDEX® and VIDEX® EC    (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine,    zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate,    elvucitabine, alovudine, phosphazid, fozivudine tidoxil,    apricitabine, KP-1461, fosalvudine tidoxil, tenofovir, tenofovir    disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil    hemifumarate, tenofovir alafenamide, tenofovir alafenamide    hemifumarate, tenofovir alafenamide fumarate, adefovir, adefovir    dipivoxil, and festinavir;    -   (5) HIV integrase inhibitors selected from the group consisting        of curcumin, derivatives of curcumin, chicoric acid, derivatives        of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of        3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives        of aurintricarboxylic acid, caffeic acid phenethyl ester,        derivatives of caffeic acid phenethyl ester, tyrphostin,        derivatives of tyrphostin, quercetin, derivatives of quercetin,        raltegravir, elvitegravir, dolutegravir and cabotegravir;-   (6) HIV non-catalytic site, or allosteric, integrase inhibitors    (NCINI) selected from the group consisting of CX-05168, CX-05045 and    CX-14442;-   (7) HIV gp41 inhibitors selected from the group consisting of    enfuvirtide, sifuvirtide and albuvirtide;-   (8) HIV entry inhibitors selected from the group consisting of    cenicriviroc;-   (9) HIV gp120 inhibitors selected from the group consisting of    Radha-108 (Receptol) and BMS-663068;-   (10) CCR5 inhibitors selected from the group consisting of    aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, Adaptavir    (RAP-101), nifeviroc (TD-0232), TD-0680, and vMIP (Haimipu);-   (11) CD4 attachment inhibitors selected from the group consisting of    ibalizumab;-   (12) CXCR4 inhibitors selected from the group consisting of    plerixafor, ALT-1188, vMIP and Haimipu;-   (13) Pharmacokinetic enhancers selected from the group consisting of    cobicistat and ritonavir,-   (14) Immune-based therapies selected from the group consisting of    dermaVir, interleukin-7, plaquenil (hydroxychloroquine), proleukin    (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon    alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea,    mycophenolate mofetil (MPA) and its ester derivative mycophenolate    mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymer    polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like    receptors modulators (TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7,    TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13), rintatolimod and IR-103;-   (15) HIV vaccines selected from the group consisting of peptide    vaccines, recombinant subunit protein vaccines, live vector    vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion    vaccine), CD4-derived peptide vaccines, vaccine combinations, rgp120    (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144),    monomeric gp120 HIV-1 subtype C vaccine (Novartis), Remune, ITV-1,    Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409, Vacc-4x,    Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5),    Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, HIV-TriMix-mRNA vaccine,    AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51,    poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06),    AGS-004, gp40[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag    vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2,    NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAVI-PG9DP, GOVX-B11,    GOVX-B21, ThV-01, TUTI-6, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade    C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H,    MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MVATG-17401,    ETV-0.1, CDX-1401, rcAd26.MOS1.HIV-Env and DNA-Ad5 gag/pol/nef/nev    (HVTN505);-   (16) HIV antibodies, bispecific antibodies and antibody-like    therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®,    TandAbs®, Fab derivatives) including BMS-936559, TMB-360 and those    targeting HIV gp120 or gp41 selected from the group consisting of    bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10,    3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2,    10E8, VRC-07-523 and VRC07;-   (17) latency reversing agents selected from the group consisting of    Histone deacetylase inhibitors such as Romidepsin, vorinostat,    panobinostat; Proteasome inhibitors such as Velcade; protein kinase    C (PKC) activators such as Indolactam, Prostratin, Ingenol B and    DAG-lactones, Ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15,    JQ1, disulfram, and amphotericin B;-   (18) HIV nucleocapsid p7 (NCp7) inhibitors selected from the group    consisting of azodicarbonamide;-   (19) HIV maturation inhibitors selected from the group consisting of    BMS-955176 and GSK-2838232;-   (20) PI3K inhibitors selected from the group consisting of    idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib,    rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib,    duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584,    copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,    panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093,    pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,    RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib,    LY-3023414, SAR-260301 and CLR-1401;-   (21) the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO    2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO    2013/006738 (Gilead Sciences), US 2013/0165489 (University of    Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan    Tobacco), WO 2013/006792 (Pharma Resources), WO 2009/062285    (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO    2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead    Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead    Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead    Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498    (Gilead Sciences); and-   (22) other drugs for treating HIV selected from the group consisting    of BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP 9, CYT-107,    alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan,    Gamimune, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN,    VSSP, Hiviral, IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43,    MK-1376, rHIV7-sh1-TAR-CCR5RZ, MazF gene therapy, BlockAide,    ABX-464, SCY-635, naltrexone, AAV-eCD4-Ig gene therapy, TEV-901.10,    TEV-90112, TEV-90111, TEV-90113, deferiprone, HS-10234, and    PA-1050040 (PA-040).

In certain embodiments, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with one, two, three, fouror more additional therapeutic agents. In certain embodiments, acompound disclosed herein (e.g. any crystalline form of Compound I), iscombined with two additional therapeutic agents. In other embodiments, acompound disclosed herein (e.g. any crystalline form of Compound I), iscombined with three additional therapeutic agents. In furtherembodiments, a compound disclosed herein (e.g. any crystalline form ofCompound I), is combined with four additional therapeutic agents. Theone, two, three, four or more additional therapeutic agents can bedifferent therapeutic agents selected from the same class of therapeuticagents, and/or they can be selected from different classes oftherapeutic agents. In a specific embodiment, a compound disclosedherein (e.g. any crystalline form of Compound I), is combined with anHIV nucleoside or nucleotide inhibitor of reverse transcriptase and anHIV non-nucleoside inhibitor of reverse transcriptase. In anotherspecific embodiment, a compound disclosed herein (e.g. any crystallineform of Compound I), is combined with an HIV nucleoside or nucleotideinhibitor of reverse transcriptase, and an HIV protease inhibitingcompound. In a further embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, an HIV non-nucleosideinhibitor of reverse transcriptase, and an HIV protease inhibitingcompound. In an additional embodiment, a compound disclosed herein (e.g.any crystalline form of Compound I), is combined with an HIV nucleosideor nucleotide inhibitor of reverse transcriptase, an HIV non-nucleosideinhibitor of reverse transcriptase, and a pharmacokinetic enhancer. Incertain embodiments, a compound disclosed herein (e.g. any crystallineform of Compound I), is combined with at least one HIV nucleosideinhibitor of reverse transcriptase, an integrase inhibitor, and apharmacokinetic enhancer. In another embodiment, a compound disclosedherein (e.g. any crystalline form of Compound I), is combined with twoHIV nucleoside or nucleotide inhibitors of reverse transcriptase.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with one, two, three, fouror more additional therapeutic agents selected from Triumeq®(dolutegravir+abacavir+lamivudine), dolutegravir+abacavirsulfate+lamivudine, raltegravir, raltegravir+lamivudine, Truvada®(tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc,enfuvirtide, Epzicom® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC),Trizivir® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC),adefovir, adefovir dipivoxil, Stribild®(elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine),rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®,rilpivirine+tenofovir disoproxil fumarate+emtricitabine), Cobicistat,atazanavir sulfate+cobicistat, atazanavir+cobicistat,darunavir+cobicistat, Atripla® (efavirenz+tenofovir disoproxilfumarate+emtricitabine), atazanavir, atazanavir sulfate, dolutegravir,elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir), ritonavir,emtricitabine, atazanavir sulfate+ritonavir, darunavir, lamivudine,Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir®(zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir, nelfinavirmesylate, interferon, didanosine, stavudine, indinavir, indinavirsulfate, tenofovir+lamivudine, zidovudine, nevirapine, saquinavir,saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir,delavirdine, delavirdine mesylate, Radha-108 (Receptol), H1viral,lamivudine+tenofovir disoproxil fumarate, efavirenz+lamivudine+tenofovirdisoproxil fumarate, phosphazid, lamivudine+nevirapine+zidovudine,abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovirdisoproxil fumarate, darunavir+cobicistat, atazanavirsulfate+cobicistat, atazanavir+cobicistat, tenofovir alafenamide andtenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with abacavir sulfate,tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with tenofovir, tenofovirdisoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, ortenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with a first additionaltherapeutic agent selected from the group consisting of: abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, and tenofovir alafenamide hemifumarate and asecond additional therapeutic agent selected from the group consistingof emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with a first additionaltherapeutic agent selected from the group consisting of: tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, and tenofovir alafenamide hemifumarate and a secondadditional therapeutic agent, wherein the second additional therapeuticagent is emtricitabine.

In certain embodiments, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with 5-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide and 200 mg emtricitabine. In certain embodiments, a compounddisclosed herein (e.g. any crystalline form of Compound I), is combinedwith 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide and 200 mg emtricitabine. In certain embodiments, a compounddisclosed herein (e.g. any crystalline form of Compound I), is combinedwith 10 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein (e.g. any crystallineform of Compound I), is combined with 25 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamideand 200 mg emtricitabine. A compound as disclosed herein (e.g., anycrystalline form of Compound I) may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 50 mg to 500 mgof compound) the same as if each combination of dosages werespecifically and individually listed.

In certain embodiments, a compound disclosed herein (e.g. anycrystalline form of Compound I), is combined with 200-400 mg tenofovirdisoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovirdisoproxil and 200 mg emtricitabine. In certain embodiments, a compounddisclosed herein (e.g. any crystalline form of Compound I), is combinedwith 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein (e.g. any crystallineform of Compound I), is combined with 300 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and200 mg emtricitabine. A compound as disclosed herein (e.g. anycrystalline form of Compound I) may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 1 mg to 500 mgof compound) the same as if each combination of dosages werespecifically and individually listed.

In certain embodiments, when a compound disclosed herein is combinedwith one or more additional therapeutic agents as described above, thecomponents of the composition are administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments, a compound disclosed herein is administered withone or more additional therapeutic agents. Co-administration of acompound disclosed herein with one or more additional therapeutic agentsgenerally refers to simultaneous or sequential administration of acompound disclosed herein and one or more additional therapeutic agents,such that therapeutically effective amounts of the compound disclosedherein and one or more additional therapeutic agents are both present inthe body of the patient.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents, for example,administration of the compound disclosed herein within seconds, minutes,or hours of the administration of one or more additional therapeuticagents. For example, in some embodiments, a unit dose of a compounddisclosed herein is administered first, followed within seconds orminutes by administration of a unit dose of one or more additionaltherapeutic agents. Alternatively, in other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed by administration of a unit dose of a compound disclosed hereinwithin seconds or minutes. In some embodiments, a unit dose of acompound disclosed herein is administered first, followed, after aperiod of hours (e.g., 1-12 hours), by administration of a unit dose ofone or more additional therapeutic agents. In other embodiments, a unitdose of one or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

VIII. Examples

Abbreviations as used herein have respective meanings as follows:

Ac Acetate ACN Acetonitrile BippyPhos5-(di-tert-butylphosphino)-1′,3′,5′- triphenyl-1′H-[1,4′]bipyrazole BnBenzyl br. s Broad singlet Bu Butyl dba Dibenzylideneacetone DCMDichloromethane dd Doublet of doublets ddd Doublet of doublet ofdoublets DIPE diisopropyl ether DMF Dimethylformamide DMSODimethylsulfoxide dr Diastereomeric ratio DSC Differential scanningcalorimetry DVS Dynamic vapor sorption ee Enantiomeric excess equivEquivalents Et Ethyl EtOAc Ethyl acetate EtOH Ethanol ft Foot (length) gGram GC Gas chromatography h Hour HBV Hepatitis B virus HCV Hepatitis Cvirus HFIPA hexafluoroisopropanol HIV Human Immunodeficiency virus HPLCHigh-pressue liquid chromatography IPA Isopropyl alcohol IPAc Isopropylacetate iPr Isopropyl iPrOAc or IPAc isopropyl acetate kg Kilogram LLiter m Multiplet M Molar Me Methyl MEK methyl ethyl ketone MeOHmethanol Me-THF 2 methyl tetrahydrofuran mg Milligram MHz Mega hertzMIBK Methylisobutyl ketone min Minute mL Milliliter mmol Millimole molMole MTBE Methyl-tert-butyl ether N Normal NLT No less than NMR Nuclearmagnetic resonance Ph Phenyl RH Relative humidity s Singlet t-Butert-Butyl td Triplet of doublets Tf Trifluoromethanesulfonate TFEtrifluoroethanol TGA Thermogravimetric analysis THF Tetrahydrofuran TMSTrimethylsilyl vol Volume wt Weight XRPD X-ray powder diffraction δChemical shift μL Microliter

The solid forms (polymorphs, solvates and hydrates) of Compound I werecharacterized by a variety of the following methods.

X-ray Powder Diffraction (XRPD). The Rigaku Smart-Lab® X-ray diffractionsystem was configured for reflection BraggBrentano geometry using a linesource X-ray beam. The x-ray source is a Cu Long Fine Focus tube thatwas operated at 40 kV and 44 mA. That source provides an incident beamprofile at the sample that changes from a narrow line at high angles toa broad rectangle at low angles. Beam conditioning slits were used onthe line X-ray source to ensure that the maximum beam size is less than10 mm both along the line and normal to the line. The Bragg-Brentanogeometry is a para-focusing geometry controlled by passive divergenceand receiving slits with the sample itself acting as the focusingcomponent for the optics. The inherent resolution of Bragg-Brentanogeometry is governed in part by the diffractometer radius and the widthof the receiving slit used. Typically, the Rigaku Smart-Lab is operatedto give peak widths of 0.1°2θ or less. The axial divergence of the X-raybeam is controlled by 5.0-degree Soller slits in both the incident anddiffracted beam paths.

Powder samples were prepared in a low background Si holder using lightmanual pressure to keep the sample surfaces flat and level with thereference surface of the sample holder. The single-crystal, Si,low-background holder has a small circular recess (7 mm diameter andabout 1 mm depth) that holds between 5 and 10 mg of powdered material.Each sample was analyzed from 2 to 40°2θ using a continuous scan of 3°2θper minute with an effective step size of 0.02°2θ.

Solubility Estimations. Solubilities were estimated by treating aweighed sample of Compound I with measured aliquots of the test solventat ambient temperature, with shaking and/or sonication between aliquots.Dissolution was determined by visual inspection. Solubility numbers werecalculated by dividing the total amount of solvent used to dissolve thesample by the weight of the sample. The actual solubilities may begreater than the numbers calculated because of the use of solventaliquots that were too large or because of slow dissolution rates. Thesolubility number is expressed as less than if dissolution did not occurduring the experiment. The solubility number is expressed as greaterthan if dissolution occurred on addition of the first solvent aliquot.

Differential Scanning Calorimetry (DSC). DSC analyses were carried outusing a TA Instruments Q2000 instrument. The instrument temperaturecalibration was performed using indium. The DSC cell was kept under anitrogen purge of ˜50 mL per minute during each analysis. The sample wasplaced in a standard, crimped, aluminum pan and was heated from 20° C.to 350° C. at a rate of 10° C. per minute.

Thermogravimetric (TGA) Analysis. The TGA analysis was carried out usinga TA Instruments Q50 instrument. The instrument balance was calibratedusing class M weights and the temperature calibration was performedusing alumel. The nitrogen purge was ˜40 ml per minute at the balanceand ˜60 ml per minute at the furnace. Each sample was placed into apretared platinum pan and heated from 20° C. to 350° C. at a rate of 10°C. per minute.

Karl Fischer (KF) Analyses. Karl Fischer analyses were carried out usinga Mettler-Toledo C20 Coulometric KF titrator. The instrument wascalibrated with a standard of known water concentration.

Dynamic Vapor Sorption (DVS). DVS analyses were carried out in a TAInstruments 05000 Dynamic Vapor Sorption analyzer. The instrument wascalibrated with standard weights and a sodium bromide standard forhumidity. Samples were analyzed at 25° C. with a maximum equilibrationtime of 60 minutes in 10% relative humidity (RH) steps from 5 to 95% RH(adsorption cycle) and from 95 to 5% RH (desorption cycle).

Example 1 Stable Form Screening of Compound I

Method I. 50 mg of Compound I was dissolved in 1 mL ofmethanol/dichloromethane, agitated, and then evaporated.

Method II. A solution of Compound I, methanol and dichloromethane, wasconcentrated under vacuum at 40° C. to about 10 volumes. Methanol wascharged and the reaction mixture was concentrated under vacuum at 40° C.to about 10 volumes (and repeated once). The slurry was agitated at 20°C. for at least 2 hours. The slurry was filtered and the filter cake wasrinsed with methanol and ethyl acetate. The wet product was dried undervacuum at NMT 40° C.

Form I is characterized by the X-ray powder diffraction pattern in FIG.1, and the differential scanning calorimetry plot in FIG. 3 showingendotherms at about 133 (conversion to Form III), 170 and 273° C.(decomposition).

Form II is characterized by the X-ray powder diffraction pattern in FIG.5, and the differential scanning calorimetry plot in FIG. 7 showingendotherms at about 98° C. (conversion to Form IV), 253° C. and 274° C.(decomposition).

Form III was generated at 138° C. from Form I in a variable temperatureXRD (VT XRD) experiment. Form III is stable when cooled to 25° C. anddoes not convert back to Form I. Form III was converted back to Form Iin a competition slurry experiment with Form I in methanol within about2 weeks (10 mg of each of Form I and Form III in methanol). Form III ischaracterized by the X-ray powder diffraction pattern in FIG. 9, and thedifferential scanning calorimetry plot in FIG. 11 showing endotherms atabout 181 and 271° C. (decomposition).

Form IV was generated between 95 and 110° C. from Form II in a variabletemperature XRD experiment. Form IV converts back to Form II when cooledto 25° C. in the VT XRD experiment. Form III is characterized by theX-ray powder diffraction pattern in FIG. 13.

Example 2 Preparation of Form I

Compound I Form I was prepared by dissolving Compound I in amethanol/dichloromethane mixture (33% MeOH/DCM) followed by reducing thevolume and dichloromethane content by distillation. Solids werecollected by vacuum filtration, resulting in Compound I Form I, asidentified by XRPD.

Example 3 Preparation of Form II

Compound I Form II was made by slurrying Compound I Form I in chloroformat ambient temperature and pressure for 5 days. Solids were collected byvacuum filtration, resulting in Compound I Form II, as identified byXRPD. Compound I Form II was also prepared by cooling Compound I Form IVto approximately 25° C. during VT-XRPD analysis. Compound I Form II wasalso prepared by heating Compound I Form XIII to approximately 11° C.

Example 4 Preparation of Form III

Compound I Form III was made by heating Compound I Form I toapproximately 150° C. during VT-XRPD analysis. Compound I Form III wasalso prepared at a lower temperature during VT-XRPD analysis whenCompound I Form I was heated to and held at 100° C.

Example 5 Preparation of Form IV

Compound I Form IV was made by heating Compound I Form II toapproximately 95° C. to 110° C. during VT-XRPD analysis. Compound I FormIV was also prepared during VT-XRPD analysis when Compound I Form IIIwas heated to approximately 180° C.

Example 6 Preparation of Form V

Compound I Form V was made by forming a solution of Compound I in HFIPA(hexafluoroisopropanol), and evaporating to dryness. An alternative wayof preparing Form V is to pour the solution of Compound I in HFIPA at100° C. into cold water and isolate the solid.

Example 7 Preparation of Form VI

Compound I Form V was made by forming a solution of Compound I in TFE(2,2,2-trifluoroethanol), and evaporating to dryness.

Example 8 Preparation of Form VII

Compound I Form V was made by forming a solution of Compound I in TFE(2,2,2-trifluoroethanol), and evaporating to dryness.

Example 9 Preparation of Form VIII

Compound I Form V was made by exposing Form V or Form VII to 97% RH atroom temperature for 1 week.

Example 10 Preparation of Form IX

Form IX was made by slurring approximately Form I of Compound I in 5:1TFE/water at ambient temperature for 5 days. Solids were collected byvacuum filtration and dried under reduced pressure for a couple minutes,resulting in Form IX, as identified by XRPD.

Example 11 Preparation of Form X

Form X was made by dissolving approximately Form I of Compound I inchloroform. The resulting solution was filtered through a 0.2 μm nylonfilter and placed in the CentriVap. The sample was centrifuged undervacuum for approximately 30 minutes at ambient temperature. Theresulting solids were identified as Form X by XRPD.

Example 12 Preparation of Form XI

Form XI was made by dissolving Form I of Compound I in HFIPA. Methanolwas then added to the solution, which resulted in a cloudy, whitesuspension. Solids were collected by vacuum filtration and dried underreduced pressure, and were identified as Form XI by XRPD.

Example 13 Preparation of Form XII

Form XII was made by forming a slurry of Form I of Compound I in 10:1TFE/water at ambient temperature for 3 days. Solids were collected byvacuum filtration and dried under reduced pressure, and were identifiedas Form XII by XRPD.

Example 14 Preparation of Form XIII

Form XIII was made by cooling Form II to −10° C.

Example 15 Preparation of Form XIV

Form XIV was made by exposing Form XII of Compound I to vacuum underambient conditions for three days, then exposing the sample to 40° C.for approximately two hours. Resulting solids were identified as FormXIV by XRPD.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference, including all of the U.S.patents, U.S. patent application publications, U.S. patent applications,foreign patents, foreign patent applications and non-patent publicationsreferred to in this specification are incorporated herein by reference,in their entirety, to the extent not inconsistent with the presentdescription. Where a conflict exists between the instant application anda reference provided herein, the instant application shall dominate.

1. A crystalline form of Compound I having the structure:

and solvates or hydrates thereof.
 2. The crystalline form of claim 1,characterized by an X-ray powder diffraction (XRPD) pattern comprisingthree or more peaks at 5.8, 11.4, 11.6, 17.7, 22.3, 23.9 or 26.0 degrees2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.3. The crystalline form of claim 1, characterized by an XRPD patterncomprising peaks at 5.8, 11.4, and 11.6 degrees 2θ (0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation.
 4. The crystallineform of claim 1, characterized by an XRPD pattern comprising peaks at5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 and 26.8 degrees 2θ(±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation. 5.The crystalline form of any of claim 1, characterized by the XRPDpattern substantially in accordance with that of FIG.
 1. 6. Thecrystalline form of claim 1, characterized by one or more differentialscanning calorimetry (DSC) endotherms at about 133° C. or about 170° C.7. The crystalline form of any of claim 1, characterized by an XRPDpattern comprising peaks at 5.8, 11.4, and 11.6 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation; and DSCendotherms at about 133° C. and about 170° C.
 8. The crystalline form ofclaim 1, characterized by an X-ray powder diffraction (XRPD) patterncomprising three or more peaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2,19.9, 22.4, 25.5 or 29.1 degrees 2θ (±0.2 degrees 2θ), wherein the XRPDis made using CuK_(α1) radiation.
 9. The crystalline form of claim 1,characterized by an XRPD pattern comprising peaks at 4.6, 18.3, 19.9,22.4 and 25.5 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is madeusing CuK_(α1) radiation.
 10. The crystalline form of claim 1,characterized by an XRPD pattern comprising peaks at 4.6, 9.2, 15.8,17.8, 18.3, 19.2, 19.9, 22.4, 25.5 and 29.1 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation.
 11. Thecrystalline form of claim 1, characterized by the XRPD patternsubstantially in accordance with that of FIG.
 5. 12. The crystallineform of claim 1, characterized by one or more differential scanningcalorimetry (DSC) endotherms at about 98° C. or about 253° C.
 13. Thecrystalline form of claim 1, characterized by an XRPD pattern comprisingpeaks at 4.6, 18.3, 19.9, 22.4, and 25.5 degrees 2θ (±0.2 degrees 2θ),wherein the XRPD is made using CuK_(α1) radiation; and DSC endotherms atabout 98° C. and about 253° C.
 14. The crystalline form of claim 1,characterized by an X-ray powder diffraction (XRPD) pattern comprisingthree or more peaks at 5.0, 10.1, 16.9, 20.3, 21.5, 22.0, 23.9 or 25.2degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation.
 15. The crystalline form of claim 1, characterized by an XRPDpattern comprising peaks at 5.0, 21.5, and 22.0 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation.
 16. Thecrystalline form of claim 1, characterized by an XRPD pattern comprisingpeaks at 5.0, 10.1, 15.2, 16.9, 20.3, 21.5, 22.0, 23.9, 25.2 and 29.4degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation.
 17. The crystalline form of claim 1, characterized by theXRPD pattern substantially in accordance with that of FIG.
 9. 18. Thecrystalline form of claim 1, characterized by a differential scanningcalorimetry (DSC) endotherm at about 181° C.
 19. The crystalline form ofclaim 1, characterized by an XRPD pattern comprising peaks at 5.0, 21.5,and 22.0 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation; and a DSC endotherm at about 181° C.
 20. Thecrystalline form of claim 1, characterized by an X-ray powderdiffraction (XRPD) pattern comprising peaks at 4.1, 18.1, 18.7, 23.8,and 26.6 degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made usingCuK_(α1) radiation.
 21. The crystalline form of claim 1, characterizedby an XRPD pattern comprising peaks at 4.1, 8.8, 16.8, 18.1, 18.7, 19.7,21.1, 21.4, 23.8, and 26.6 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation.
 22. The crystalline form of claim1, characterized by the XRPD pattern substantially in accordance withthat of FIG.
 13. 23. The crystalline form of claim 1, characterized byan X-ray powder diffraction (XRPD) pattern comprising three or morepeaks at 5.3, 9.8, 13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 or 24.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation.
 24. The crystalline form of claim 1 23, characterized by anXRPD pattern comprising peaks at 5.3, 9.8 and 15.6 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.
 25. Thecrystalline form of claim 1, characterized by an XRPD pattern comprisingpeaks at 5.3, 9.8, 13.1, 15.6, 17.0, 19.6, 20.0, 20.7, 21.9 and 24.9degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation.
 26. The crystalline form of claim 1, characterized by theXRPD pattern substantially in accordance with that of FIG.
 20. 27. Thecrystalline form of claim 1, characterized by a differential scanningcalorimetry (DSC) endotherm at about 141° C. or about 173° C.
 28. Thecrystalline form of claim 1, characterized by an XRPD pattern comprisingpeaks at 5.3, 9.8, and 15.6 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation; and a DSC endotherm at about 173°C.
 29. The crystalline form of claim 1, characterized by an X-ray powderdiffraction (XRPD) pattern comprising three or more peaks at 5.5, 9.4,10.8, 11.9, 12.9, 14.4, 16.0, 19.0, 21.9, or 23.9 degrees 2θ (±0.2degrees 2θ), wherein the XRPD is made using CuK_(α1) radiation.
 30. Thecrystalline form of claim 1, characterized by an XRPD pattern comprisingpeaks at 5.5, 10.8 and 16.0 degrees 2θ (±0.2 degrees 2θ), wherein theXRPD is made using CuK_(α1) radiation.
 31. The crystalline form of claim1, characterized by an XRPD pattern comprising peaks at 5.5, 9.4, 10.8,1.1.9, 12.9, 14.4, 16.0, 19.0, 21.9, and 23.9 degrees 2θ (±0.2 degrees2θ), wherein the XRPD is made using CuK_(α1) radiation.
 32. Thecrystalline form of claim 1, characterized by the XRPD patternsubstantially in accordance with that of FIG.
 23. 33. The crystallineform of claim 1, characterized by a differential scanning calorimetry(DSC) endotherm at about 142° C.
 34. The crystalline form of claim 1,characterized by an XRPD pattern comprising peaks at 5.5, 10.8, and 16.0degrees 2θ (±0.2 degrees 2θ), wherein the XRPD is made using CuK_(α1)radiation; and a DSC endotherm at about 142° C.
 35. A method ofpreparing a crystalline Form I of the compound of claim 1, comprising:forming a mixture comprising the compound of claim 1, and a solventcomprising a C₁-C₃ alcohol and dichloromethane, under conditionssuitable to prepare Form I.
 36. The method of claim 35, wherein thesolvent comprises one of methanol, ethanol, or isopropanol.
 37. Themethod of claim 35, wherein the solvent comprises methanol anddichloromethane.
 38. The method of claim 35, wherein the method furthercomprises evaporating the solvent, thereby forming Form I.
 39. A methodof preparing a crystalline Form II of the compound of claim 1,comprising: forming a mixture comprising a Form I of the compound ofclaim 1, and chloroform, under conditions suitable to prepare Form II.40. A method of preparing a crystalline Form III of the compound ofclaim 1, comprising: heating a Form I of the compound of claim 1 to atemperature of from about 130° C. to about 190° C., thereby preparingForm III.
 41. The method of claim 40, further comprising cooling FormIII to room temperature.
 42. A method of preparing a crystalline Form IVof the compound of claim 1, comprising: heating a Form II of thecompound of claim 1 to a temperature of from about 90° C. to about 250°C., thereby preparing Form IV.
 43. A method of preparing a crystallineForm IX of the compound of claim 1, comprising: forming a mixturecomprising a Form I of the compound of claim 1, water andtrifluoroethanol, under conditions suitable to prepare Form IX.
 44. Themethod of claim 43, wherein the ratio of trifluoroethanol to water isfrom about 10:1 to about 1:1 (volume/volume).
 45. The method of claim43, wherein the ratio of trifluoroethanol to water is about 5:1(volume/volume).
 46. A method of preparing a crystalline Form X of thecompound of claim 1, comprising: forming a mixture comprising a Form Iof the compound of claim 1 and chloroform, under conditions suitable toprepare Form X.
 47. A pharmaceutical composition comprising atherapeutically effective amount of a crystalline form of Compound I ofclaim 1, and a pharmaceutically acceptable carrier or excipient.
 48. Thecomposition of claim 47, wherein the crystalline form of Compound I isthe crystalline form of claim
 3. 49. The composition of claim 47,further comprising at least one additional therapeutic agent selectedfrom the group consisting of HBV combination drugs, HBV DNA polymeraseinhibitors, immunomodulators, toll-like receptor modulators (modulatorsof TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11,TLR12 and TLR13), interferon alpha receptor ligands, hyaluronidaseinhibitors, recombinant IL-7, hepatitis B surface antigen (HBsAg)inhibitors, hepatitis B surface antigen (HBsAg) secretion or assemblyinhibitors, compounds targeting hepatitis B core antigen (HBcAg),cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylacticvaccines, HBV viral entry inhibitors, NTCP (Na+-taurocholatecotransporting polypeptide) inhibitors, antisense oligonucleotidetargeting viral mRNA, short interfering RNAs (siRNA), miRNA gene therapyagents, endonuclease modulators, inhibitors of ribonucleotide reductase,hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A(SRA) proteins, Src kinase inhibitors, HBx inhibitors, cccDNAinhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodiesincluding HBV antibodies targeting the surface antigens of the hepatitisB virus and bispecific antibodies and “antibody-like” therapeuticproteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fabderivatives, TCR-like antibodies), CCR2 chemokine antagonists, thymosinagonists, cytokines, nucleoprotein modulators (HBV core or capsidprotein modulators), stimulators of retinoic acid-inducible gene 1,stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors, STINGagonists, PI3K inhibitors, lymphotoxin beta receptor activators, NaturalKiller Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein4 (CTLA4) inhibitors, IDO inhibitors, cccDNA epigenetic modifiers, CD137inhibitors, Killer cell lectin-like receptor subfamily G member 1inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors,CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-InterferonLambda, recombinant thymosin alpha-1, BTK inhibitors, modulators ofTIGIT, modulators of CD47, modulators of SIRPalpha, modulators of ICOS,modulators of CD27, modulators of CD70, modulators of OX40, modulatorsof NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3,modulators of NKG2A, modulators of GITR, modulators of CDI60, modulatorsof HEVEM, modulators of CDI61, modulators of Ax1, modulators of Mer,modulators of Tyro, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs),IAPs inhibitors, SMAC mimetics, and Hepatitis B virus replicationinhibitors compounds.
 50. The composition of claim 47, furthercomprising at least one additional therapeutic agent selected from thegroup consisting of (1) Combination drugs selected from the groupconsisting of tenofovir disoproxil fumarate+emtricitabine (TRUVADA®),ABX-203+lamivudine+PEG-IFNalpha, and ABX-203+adefovir+PEG-IFNalpha,INO-9112+RG7944 (INO-1800); (2) HBV DNA polymerase inhibitors selectedfrom the group consisting of besifovir, entecavir (Baraclude®), adefovir(Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil,tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester,telbivudine (Tyzeka®), pradefovir, Clevudine, emtricitabine (Emtriva®),ribavirin, lamivudine (Epivir-HBV®), phosphazide, famciclovir,SNC-019754, FMCA, fusolin, AGX-1009, AR-II-04-26, HS-10234 andmetacavir; (3) Immunomodulators selected from the group consisting ofrintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil(hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil(MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10,ribavirin, IL-12, INO-9112, polymer polyethyleneimine (PEI), Gepon,VGV-1, MOR-22, BMS-936559, RO-7011785, RO-6871765 and IR-103; (4)Toll-like receptor 7 modulators selected from the group consisting ofGS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025,IMO-4200, MCT-465, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202RG-7863 and RG-7795; (5) Toll-like receptor 8 modulators selected fromthe group consisting of motolimod, resiquimod, 3M-051, 3M-052, MCT-465,IMO-4200, VTX-763, and VTX-1463; (6) Toll-like receptor 3 modulatorsselected from the group consisting of rintatolimod, poly-ICLC, MCT-465,MCT-475, Riboxxon, Riboxxim and ND-1.1; (7) Interferon alpha receptorligands selected from the group consisting of interferon alpha-2b(Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alpha1b (Hapgen®), Veldona, Infradure, Roferon-A, YPEG-interferon alfa-2a(YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferongamma), rSIFN-co (recombinant super compound interferon), Ypeginterfemnalfa-2b (YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b(PEG-Intron®), Bioferon, Novaferon, Inmutag (Inferon), Multiferon®,interferon alfa-n1 (Humoferon®), interferon beta-1a (Avonex®), Shaferon,interferon alfa-2b (AXXO), Altfaferone, interferon alfa-2b (BioGenericPharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-B,BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-BPDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma),alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferonalfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferonalfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b(Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b(Changchun Institute of Biological Products), Anterferon, Shanferon,Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat,rHSA-IFN alpha-2b and Interapo (Interapa); (8) Hyaluronidase inhibitorsselected from the group consisting of astodrimer; (9) Modulators ofIL-10; (10) HBsAg inhibitors selected from the group consisting ofHBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9,REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053,REP-2031, REP-006 and REP-9AC′; (11) Toll like receptor 9 modulatorsselected from CYT003 and CYT-003-QbG10; (12) Cyclophilin inhibitorsselected from the group consisting of OCB-030, SCY-635 and NVP-018; (13)HBV Prophylactic vaccines selected from the group consisting of Hexaxim,Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M(LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L,DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylacticvaccine (Advax Super D), Hepatrol-07, GSK-223192A, Engerix B,recombinant hepatitis B vaccine (intramuscular, Kangtai BiologicalProducts), recombinant hepatitis B vaccine (Hansenual polymorpha yeast,intramuscular, Hualan Biological Engineering), Bimmugen, Euforavac,Eutravac, anrix-DTaP-IPV-Hep B, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, InfanrixHep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, HeberbiovacHB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine, andDTaP-rHB-Hib vaccine; (14) HBV Therapeutic vaccines selected from thegroup consisting of HBsAG-HBIG complex, Bio-Hep-B, NASVAC, abi-HB(intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine(epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac Bmcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02,FP-02.2, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine,Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinantVLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909,AdTG-17910 AdTG-18202, ChronVac-B, and Lm HBV; (15) HBV viral entryinhibitor selected from the group consisting of Myrcludex B; (16)Antisense oligonucleotide targeting viral mRNA selected from the groupconsisting of ISIS-HBVRx; (17) short interfering RNAs (siRNA) selectedfrom the group consisting of TKM-HBV (TKM-HepB), ALN-HBV, SR-008, ddRNAiand ARC-520; (18) Endonuclease modulators selected from the groupconsisting of PGN-514; (19) Inhibitors of ribonucleotide reductaseselected from the group consisting of Trimidox; (20) Hepatitis B virus Eantigen inhibitors selected from the group consisting of wogonin; (21)HBV antibodies targeting the surface antigens of the hepatitis B virusselected from the group consisting of GC-1102, XTL-17, XTL-19, XTL-001,KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy(hepatitis B virus infection, Humabs BioMed); (22) HBV antibodiesincluding monoclonal antibodies and polyclonal antibodies selected fromthe group consisting of Zutectra, Shang Sheng Gan Di, Uman Big(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B,igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4,HBV infection, Shanghai RAAS Blood Products) and Fovepta (BT-088); (23)CCR2 chemokine antagonists selected from the group consisting ofpropagermanium; (24) Thymosin agonists selected from the groupconsisting of Thymalfasin; (25) Cytokines selected from the groupconsisting of recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex);recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24and celmoleukin; (26) Nucleoprotein modulators (HBV core or capsidprotein modulators) selected from the group consisting of NVR-1221,NVR-3778, BAY 41-4109, morphothiadine mesilate and DVR-23; (27)Stimulators of retinoic acid-inducible gene 1 selected from the groupconsisting of SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537,ORI-9020, ORI-9198 and ORI-7170; (28) Stimulators of NOD2 selected fromthe group consisting of SB-9200; (29) Recombinant thymosin alpha-1selected from the group consisting of NL-004 and PEGylated thymosinalpha 1; (30) Hepatitis B virus replication inhibitors selected from thegroup consisting of isothiafludine, IQP-HBV, RM-5038 and Xingantie; (31)PI3K inhibitors selected from the group consisting of idelalisib,AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib,rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857,taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate,perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557,GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439,puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117,SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR-1401; (32)cccDNA inhibitors selected from the group consisting of BSBI-25; (33)PD-L1 inhibitors selected from the group consisting of MEDI-0680,RG-7446, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL,STI-A1014 and BMS-936559; (34) PD-1 inhibitors selected from the groupconsisting of nivolumab, pembrolizumab, pidilizumab, BGB-108 andmDX-400; (35) BTK inhibitors selected from the group consisting ofACP-196, dasatinib, ibrutinib, PRN-1008, SNS-062, ONO-4059, BGB-3111,MSC-2364447, X-022, spebrutinib, TP-4207, HM-71224, KBP-7536 andAC-0025; (36) IDO inhibitors selected from the group consisting ofepacadostat (INCB24360), F-001287, resminostat (4SC-201), SN-35837,NLG-919, GDC-0919, and indoximod; and (37) Other drugs for treating HBVselected from the group consisting of gentiopicrin (gentiopicroside),nitazoxanide, birinapant, NOV-205 (Molixan; BAM-205), Oligotide,Mivotilate, Feron, levamisole, Ka Shu Ning, Alloferon, WS-007, Y-101 (TiFen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid,HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna,IBPB-0061A, Hepuyinfen, DasKloster 0014-01, Jiangantai (Ganxikang),picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reducedglutathione, RO-6864018 and ZH-2N.
 51. A method of treating a viralinfection, comprising administering to a human in need thereof, atherapeutically effective amount of a crystalline form of Compound I ofclaim
 1. 52. The method of claim 51, wherein the viral infection iscaused by Hepatitis B virus.
 53. The method of claim 51, furthercomprising administering at least one additional therapeutic agentselected from the group consisting of HBV combination drugs, HBV DNApolymerase inhibitors, immunomodulators, toll-like receptor modulators(modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9,TLR10, TLR11, TLR12 and TLR13), interferon alpha receptor ligands,hyaluronidase inhibitors, recombinant IL-7, hepatitis B surface antigen(HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion orassembly inhibitors, compounds targeting hepatitis B core antigen(HBcAg), cyclophilin inhibitors, HBV therapeutic vaccines, HBVprophylactic vaccines, HBV viral entry inhibitors, NTCP(Na+-taurocholate cotransporting polypeptide) inhibitors, antisenseoligonucleotide targeting viral mRNA, short interfering RNAs (siRNA),miRNA gene therapy agents, endonuclease modulators, inhibitors ofribonucleotide reductase, hepatitis B virus E antigen inhibitors,recombinant scavenger receptor A (SRA) proteins, Src kinase inhibitors,HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs(sshRNAs), HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies andantibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®,XmAbs®, TandAbs®, Fab derivatives, TCR-like antibodies), CCR2 chemokineantagonists, thymosin agonists, cytokines, nucleoprotein modulators (HBVcore or capsid protein modulators), stimulators of retinoicacid-inducible gene 1, stimulators of NOD2, stimulators of NOD1,Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin betareceptor activators, Natural Killer Cell Receptor 2B4 inhibitors,Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxicT-lymphocyte-associated protein 4 (CTLA4) inhibitors, IDO inhibitors,cccDNA epigenetic modifiers, CD137 inhibitors, Killer cell lectin-likereceptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- andT-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors,PD-L1 inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1,BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators ofSIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70,modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulatorsof B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of G1TR,modulators of CD160, modulators of HEVEM, modulators of CD161,modulators of Ax1, modulators of Mer, modulators of Tyro, gene modifiersor editors such as CRISPR (including CRISPR Cas9), zinc finger nucleasesor synthetic nucleases (TALENs), IAPs inhibitors, SMAC mimetics, andHepatitis B virus replication inhibitors compounds.
 54. The method ofclaim 51, further comprising administering at least one additionaltherapeutic agent selected from the group consisting of (1) Combinationdrugs selected from the group consisting of tenofovir disoproxilfumarate+emtricitabine (TRUVADA®), ABX-203+lamivudine+PEG-IFNalpha, andABX-203+adefovir+PEG-IFNalpha, INO-9112+RG7944 (INO-1800); (2) HBV DNApolymerase inhibitors selected from the group consisting of besifovir,entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxilfumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate,tenofovir octadecyloxyethyl ester, telbivudine (Tyzeka®), pradefovir,Clevudine, emtricitabine (Emtriva®), ribavirin, lamivudine(Epivir-HBV®), phosphazide, famciclovir, SNC-019754, FMCA, fusolin,AGX-1009, AR-II-04-26, HS-10234 and metacavir; (3) Immunomodulatorsselected from the group consisting of rintatolimod, imidolhydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine),proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its esterderivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12,INO-9112, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22,BMS-936559, RO-7011785, RO-6871765 and IR-103; (4) Toll-like receptor 7modulators selected from the group consisting of GS-9620, GSK-2245035,imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, 3M-051,SB-9922, 3M-052, Limtop, TMX-30X, TMX-202 RG-7863 and RG-7795; (5)Toll-like receptor 8 modulators selected from the group consisting ofmotolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, andVTX-1463; (6) Toll-like receptor 3 modulators selected from the groupconsisting of rintatolimod, poly-ICLC, MCT-465, MCT-475, Riboxxon,Riboxxim and ND-1.1; (7) Interferon alpha receptor ligands selected fromthe group consisting of interferon alpha-2b (Intron A®), pegylatedinterferon alpha-2a (Pegasys®), interferon alpha 1b (Hapgen®), Veldona,Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a),P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co(recombinant super compound interferon), Ypeginterferon alfa-2b(YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-Intron®),Bioferon, Novaferon, Inmutag (Inferon), Multiferon®, interferon alfa-n1(Humoferon®), interferon beta-1a (Avonex®), Shaferon, interferon alfa-2b(AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma),interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A,Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega),Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b(Changchun Institute of Biological Products), Anterferon, Shanferon,Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat,rHSA-IFN alpha-2b and Interapo (Interapa); (8) Hyaluronidase inhibitorsselected from the group consisting of astodrimer; (9) Modulators ofIL-10; (10) HBsAg inhibitors selected from the group consisting ofHBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9,REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053,REP-2031, REP-006 and REP-9AC′; (11) Toll like receptor 9 modulatorsselected from CYT003 and CYT-003-QbG10; (12) Cyclophilin inhibitorsselected from the group consisting of OCB-030, SCY-635 and NVP-018; (13)HBV Prophylactic vaccines selected from the group consisting of Hexaxim,Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M(LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L,DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylacticvaccine (Advax Super D), Hepatrol-07, GSK-223192A, Engerix B®,recombinant hepatitis B vaccine (intramuscular, Kangtai BiologicalProducts), recombinant hepatitis B vaccine (Hansenual polymorpha yeast,intramuscular, Hualan Biological Engineering), Bimmugen, Euforavac,Eutravac, anrix-DTaP-IPV-Hep B, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, InfanrixHep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, HeberbiovacHB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine, andDTaP-rHB-Hib vaccine; (14) HBV Therapeutic vaccines selected from thegroup consisting of HBsAG-HBIG complex, Bio-Hep-B, NASVAC, abi-HB(intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine(epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac Bmcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02,FP-02.2, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine,Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinantVLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909,AdTG-17910 AdTG-18202, ChronVac-B, and Lm HBV; (15) HBV viral entryinhibitor selected from the group consisting of Myrcludex B; (16)Antisense oligonucleotide targeting viral mRNA selected from the groupconsisting of ISIS-HBVRx; (17) short interfering RNAs (siRNA) selectedfrom the group consisting of TKM-HBV (TKM-HepB), ALN-HBV, SR-008, ddRNAiand ARC-520; (18) Endonuclease modulators selected from the groupconsisting of PGN-514; (19) Inhibitors of ribonucleotide reductaseselected from the group consisting of Trimidox; (20) Hepatitis B virus Eantigen inhibitors selected from the group consisting of wogonin; (21)HBV antibodies targeting the surface antigens of the hepatitis B virusselected from the group consisting of GC-1102, XTL-7, XTL-19, XTL-001,KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy(hepatitis B virus infection, Humabs BioMed); (22) HBV antibodiesincluding monoclonal antibodies and polyclonal antibodies selected fromthe group consisting of Zutectra, Shang Sheng Gan Di, Uman Big(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B,igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4,HBV infection, Shanghai RAAS Blood Products) and Fovepta (BT-088); (23)CCR2 chemokine antagonists selected from the group consisting ofpropagermanium; (24) Thymosin agonists selected from the groupconsisting of Thymalfasin; (25) Cytokines selected from the groupconsisting of recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex);recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24and celmoleukin; (26) Nucleoprotein modulators (HBV core or capsidprotein modulators) selected from the group consisting of NVR-1221,NVR-3778, BAY 41-4109, morphothiadine mesilate and DVR-23; (27)Stimulators of retinoic acid-inducible gene 1 selected from the groupconsisting of SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537,ORI-9020, ORI-9198 and ORI-7170; (28) Stimulators of NOD2 selected fromthe group consisting of SB-9200; (29) Recombinant thymosin alpha-1selected from the group consisting of NL-004 and PEGylated thymosinalpha 1; (30) Hepatitis B virus replication inhibitors selected from thegroup consisting of isothiafludine, IQP-HBV, RM-5038 and Xingantie; (31)PI3K inhibitors selected from the group consisting of idelalisib,AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib,rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857,taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate,perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557,GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439,puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117,SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR-1401; (32)cccDNA inhibitors selected from the group consisting of BSBI-25; (33)PD-L1 inhibitors selected from the group consisting of MEDI-0680,RG-7446, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL,STI-A1014 and BMS-936559; (34) PD-1 inhibitors selected from the groupconsisting of nivolumab, pembrolizumab, pidilizumab, BGB-108 andmDX-400; (35) BTK inhibitors selected from the group consisting ofACP-196, dasatinib, ibrutinib, PRN-1008, SNS-062, ONO-4059, BGB-3111,MSC-2364447, X-022, spebrutinib, TP-4207, HM-71224, KBP-7536 andAC-0025; (36) IDO inhibitors selected from the group consisting ofepacadostat (INCB24360), F-001287, resminostat (4SC-201), SN-35837,NLG-919, GDC-0919, and indoximod; and (37) Other drugs for treating HBVselected from the group consisting of gentiopicrin (gentiopicroside),nitazoxanide, birinapant, NOV-205 (Molixan; BAM-205), Oligotide,Mivotilate, Feron, levamisole, Ka Shu Ning, Alloferon, WS-007, Y-101 (TiFen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid,HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna,IBPB-0061A, Hepuyinfen, DasKloster 0014-01, Jiangantai (Ganxikang),picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reducedglutathione, RO-6864018 and ZH-2N.
 55. (canceled)
 56. (canceled)